Post-exposure prophylaxis (PEP) with antiretrovirals is now widely used worldwide after either occupational contact (with blood or another blood-containing fluid), or nonoccupational contact (mainly sexual or injection-drug use). It is assumed to reduce the risk of HIV transmission by at least 80%, although its efficacy has not been completely proven. Several countries have issued guidelines to help the clinician in their decision to offer PEP and to improve its cost-effectiveness. This article reviews the different antiretroviral combinations used, their safety profile, the recommendations and indications of PEP. The initial evaluation of an exposed individual is presented, as well as the follow-up during and after treatment.