Rarely, nerves or blood vessels around the injection site can be damaged, resulting in severe pain or paralysis.

Medication administered in the muscle is generally quickly absorbed in the bloodstream, and avoids the first pass metabolism which occurs with oral administration.

[4] Disadvantages of intramuscular administration include skill and technique required, pain from injection, anxiety or fear (especially in children), and difficulty in self-administration which limits its use in outpatient medicine.

For this reason, unless there are desired differences in rate of absorption, time to onset, or other pharmacokinetic parameters in the specific situation, a less invasive form of drug administration (usually by mouth) is preferred.

They are also not recommended in people who are in hypovolemic shock, or have myopathy or muscle atrophy, as these conditions may alter the absorption of the medication.

[5] The damage to the muscle caused by an intramuscular injections may interfere with the accuracy of certain cardiac tests for people with suspected myocardial infarction and for this reason other methods of administration are preferred in such instances.

[5] In people with an active myocardial infarction, the decrease in circulation may result in slower absorption from an IM injection.

[9]: 368–369  Within a specific site of administration, the injection should not be given directly over irritation or redness, birthmarks or moles, or areas with scar tissue.

If single-use or sterilized equipment is not used, there is the risk of transmission of infectious disease between users, or to a practitioner who inadvertently injures themselves with a used needle, termed a needlestick injury.

[11] The dorsogluteal site of injection is associated with a higher risk of skin and tissue trauma, muscle fibrosis or contracture, hematoma, nerve palsy, paralysis, and infections such as abscesses and gangrene.

[12] Furthermore, injection in the gluteal muscle poses a risk for damage to the sciatic nerve, which may cause shooting pain or a sensation of burning.

Damage to the sciatic nerve can be prevented by using the ventrogluteal site instead, and by selecting an appropriate size and length of needle for the injection.

Common sites for intramuscular injection include: deltoid, dorsogluteal, rectus femoris, vastus lateralis and ventrogluteal muscles.

[23] The deltoid muscle in the outer portion of the upper arm is used for injections of small volume, usually equal to or less than 1 mL.

[11] The ventrogluteal site on the hip is used for injections which require a larger volume to be administered, greater than 1 mL, and for medications which are known to be irritating, viscous, or oily.

[17] The vastus lateralis site is used for infants less than 7 months old and people who are unable to walk or who have loss of muscular tone.

[27] This site is located by dividing the buttock into four using a cross shape, and administering the injection in the upper outer quadrant.

[8] After the introduction of antibiotics in the middle of the 20th century, nurses began preparing equipment for intramuscular injections as part of their delegated duties from physicians, and by 1961 they had "essentially taken over the procedure".

[31] Until the 2000s, aspiration after inserting the needle was recommended as a safety measure, to ensure the injection was being administered in a muscle and not inadvertently in a vein.

However, this is no longer recommended as evidence shows no safety benefit and it lengthens the time taken for injection, which causes more pain.