[9][10] Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA).

[10] Serious side effects may include serotonin syndrome, bone marrow suppression, and high blood lactate levels, particularly when used for more than two weeks.

In both the popular press and the scientific literature, linezolid has been called a "reserve antibiotic"—one that should be used sparingly so that it will remain effective as a drug of last resort against potentially intractable infections.

[23] A large meta-analysis of randomized controlled trials found linezolid to be more effective than glycopeptide antibiotics (such as vancomycin and teicoplanin) and beta-lactam antibiotics in the treatment of skin and soft tissue infections (SSTIs) caused by Gram-positive bacteria,[24] and smaller studies appear to confirm its superiority over teicoplanin in the treatment of all serious Gram-positive infections.

[29] Some authors have recommended that combinations of cheaper or more cost-effective drugs (such as co-trimoxazole with rifampicin or clindamycin) be tried before linezolid in the treatment of SSTIs when susceptibility of the causative organism allows it.

Linezolid appears to be a reasonable therapeutic option for infective endocarditis caused by multi-resistant Gram-positive bacteria, despite a lack of high-quality evidence to support this use.

[53] It is also one of few antibiotics that diffuse into the vitreous humor, and may therefore be effective in treating endophthalmitis (inflammation of the inner linings and cavities of the eye) caused by susceptible bacteria.

[28] In animal studies of meningitis caused by Streptococcus pneumoniae, linezolid was found to penetrate well into cerebrospinal fluid, but its effectiveness was inferior to that of other antibiotics.

Nonetheless, it has been used successfully in many cases of central nervous system infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a reasonable choice for this indication when treatment options are limited or when other antibiotics have failed.

[59] In March 2007, the FDA reported the results of a randomized, open-label, phase III clinical trial comparing linezolid to vancomycin in the treatment of catheter-related bloodstream infections.

[23] According to one study, linezolid may need to be given more frequently than normal in people with burns affecting more than 20% of body area, due to increased nonrenal clearance of the drug.

[8][69] Some authors have noted that, despite its bacteriostatic effect in vitro, linezolid "behaves" as a bactericidal antibiotic in vivo because it inhibits the production of toxins by staphylococci and streptococci.

[56][71] Linezolid's spectrum of activity against Gram-positive bacteria is similar to that of the glycopeptide antibiotic vancomycin, which has long been the standard for treatment of MRSA infections, and the two drugs are often compared.

[74] Like nearly all antibiotics, linezolid has been associated with Clostridioides difficile-associated diarrhea (CDAD) and pseudomembranous colitis, although the latter is uncommon, occurring in about one in two thousand patients in clinical trials.

[73][77] A 2004 case report suggested that pyridoxine (a form of vitamin B6) could reverse the anemia and thrombocytopenia caused by linezolid,[78] but a later, larger study found no protective effect.

[79] Long-term use of linezolid has also been associated with chemotherapy-induced peripheral neuropathy, a progressive and enduring often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs.

[8][73] A more extensive monitoring protocol for early detection of toxicity in seriously ill patients receiving linezolid has been developed and proposed by a team of researchers in Melbourne, Australia.

The protocol includes twice-weekly blood tests and liver function tests; measurement of serum lactate levels, for early detection of lactic acidosis; a review of all medications taken by the patient, interrupting the use of those that may interact with linezolid; and periodic eye and neurological exams in patients set to receive linezolid for longer than four weeks.

Linezolid does not inhibit or induce the cytochrome P450 (CYP) system, which is responsible for the metabolism of many commonly used drugs, and therefore does not have any CYP-related interactions.

[23][54] In 2008, the crystal structure of linezolid bound to the 50S subunit of a ribosome from the archaean Haloarcula marismortui was elucidated by a team of scientists from Yale University and deposited in the Protein Data Bank.

[23] Linezolid's plasma protein binding is approximately 31% (range 4–32%) and its volume of distribution at steady state averages 36.1–47.3 liters in healthy adult volunteers.

[105] Clearance of linezolid varies with age and gender; it is fastest in children (which accounts for the shorter half-life), and appears to be 20% lower in women than in men.

[35][108] The anticoagulant rivaroxaban (Xarelto) bears a striking structural similarity to linezolid; both drugs share the oxazolidinone pharmacophore, differing in only three areas (an extra ketone and chlorothiophene, and missing the fluorine atom).

[108][110] Despite good yields, the original method (developed by Upjohn for pilot plant-scale production of linezolid and eperezolid) is lengthy, requires the use of expensive chemicals—such as palladium on carbon and the highly sensitive reagents methanesulfonyl chloride and n-butyllithium—and needs low-temperature conditions.

[114] Acquired resistance to linezolid was reported as early as 1999, in two patients with severe, multidrug-resistant Enterococcus faecium infection who received the drug through a compassionate use program.

[115] In the United States, resistance to linezolid has been monitored and tracked since 2004 through a program named LEADER, which (as of 2007[update]) was conducted in 60 medical institutions throughout the country.

Studies of the compounds' structure–activity relationships led to the development of several subclasses of oxazolidinone derivatives, with varying safety profiles and antimicrobial activity.

[72][128] Linezolid was found to have a pharmacokinetic advantage—requiring only twice-daily dosage, while eperezolid needed to be given three times a day to achieve similar exposure—and therefore proceeded to further trials.

[129] Approval followed in Brazil (June 2000),[130] the United Kingdom (January 2001),[7][73] Japan and Canada (April 2001),[131][132][133] Europe (throughout 2001),[134] and other countries in Latin America and Asia.

Studies have been conducted in several countries with different health care system models to assess the cost-effectiveness of linezolid compared to glycopeptides such as vancomycin or teicoplanin.