[2] In 2009 the journal reaffirmed its scope and noted that it would use an evidence-based approach to give highest priority to studies on diseases and risk factors that cause the greatest burden worldwide.

[7] The essay used a simulation approach to demonstrate that for most study designs and settings it is more likely for a research claim to be false than true due to inherent biases in the way that modern science is conducted.

[12] The Lancet a leading medical journal rejected this paper because of ethical concerns[13] around how the trial was conducted before PLOS Medicine accepted it.

The results of this trial along with two others led to the World Health Organization (WHO) assessing the evidence for male circumcision to prevent HIV transmission.

[18] In July 2009, a United States federal court decision resulted in the release of approximately 1500 documents detailing how articles highlighting specific marketing messages written by unattributed writers, but "authored" by academics, are strategically placed in the medical literature – a practice known as ghostwriting.

PLOS Medicine argued that sealed documents identified during the discovery process for the court case, which demonstrated the practice of ghostwriting, should be made available to the public.

[23] In April 2012 PLOS Medicine published an article by three researchers who were involved in ongoing updates of a Cochrane Collaboration review of neuraminidase inhibitors for treating influenza, describing their experience of trying to gain access to clinical study reports for the antiviral Tamiflu (oseltamivir) from the drug's manufacturer Roche.

The article marked a move towards the proactive disclosure of clinical trial data and led to the EMA holding a workshop to establish how this could be done.