A number of studies have examined the effectiveness of post-exposure prophylaxis, in animal models and in humans. While animal studies have provided evidence that using antiretroviral drugs after exposure to HIV or related viruses can prevent long-term infection, transferring these findings to humans is difficult, due to differences between species and viruses.

Studies in humans have largely concentrated on ‘occupational exposure’, usually of healthcare workers. However, more recent findings have looked at infection rates following exposure through non-occupational means, such as unprotected sex. It is not possible to carry out randomised trials comparing PEP to no treatment in humans, as this would involve denying some exposed patients treatment. Consequently, almost all of the evidence on the effectiveness of PEP in humans comes from observational studies. Although these have shown low levels of infection in potentially exposed people who take PEP, they cannot prove definitively that PEP works, as reductions in infection rates could be due to factors other than being given PEP. In addition, there is often considerable variability between patients in the likelihood of HIV transmission taking place.

Evidence for the effectiveness of PEP has also been demonstrated by prevention of mother-to-child transmission of HIV by short courses of antiretroviral drugs in newborns. This is discussed in HIV treatment during pregnancy.