Early antiretroviral chemoprophylaxis after HIV exposure can reduce the risk of transmission according to in vitro studies, animal experiments, and the results of a case control study on occupationally exposed health care workers. Additional consistent evidence comes from trials on treatment of acute infection and on prevention of vertical transmission. Combination post exposure prophylaxis (PEP) with available antiretroviral agents is recommended because of higher antiretroviral activity, and to overcome the increasing problem of resistant HIV strains. Recommendations include the addition of a second reverse transcriptase inhibitor antiretroviral agent to zidovudine for the majority of exposures and the addition of a protease inhibitor for, at least, highest risk exposures. Starting PEP as soon as possible is strongly recommended, within 1-4 hours from the exposure; the recommended duration is four-weeks. Contraindications are those specified in the package insert for each product. PEP guidelines refer to exposures occurring in health care settings. PEP can be considered in the case of rape or sexual exposure that occur in isolation in individuals committed to safe practices, as in the case of breakage of condoms in a discordant couple, or who intend to stop risk practices, as an intravenous drug user who comply to maintenance or detoxification program. PEP is not recommended in the case of injury with abandoned needles. Being the ideal PEP regimen not fully defined, there is the need to collect further information through the institution of National and International Combined PEP Registries. Because of its complexity PEP management needs high professional skills and service organisation. Moreover, the suggested guidelines can not be considered definite and post exposure policies and PEP protocols that reflect best updated practice should be ensured.