The number of people infected with HIV continues to increase relentlessly. Post-exposure prophylaxis (PEP) following exposure to HIV infection may prevent established HIV infection. Such intervention is supported by biological plausibility and limited data from animal and human studies. Antiretroviral prophylaxis is associated with significant side effects and the risk should be weighed against the potential benefits. PEP should be considered after significant occupational and non-occupational exposures. However, PEP is not suitable for individuals with repeated high-risk behaviour who are not willing to adhere to risk reduction practices. Primary prevention strategies remain the mainstay for control of the HIV epidemic and cannot be replaced by PEP. Guidance for PEP following exposure to HIV infection is available in many countries worldwide.