Thousands of health care workers are potentially exposed to human immunodeficiency virus (HIV) each year via occupationally acquired needlesticks. The Centers for Disease Control and Prevention (Atlanta, GA) advise health care workers who experience a high-risk occupational exposure from an HIV-infected patient to begin receiving multidrug antiretroviral postexposure prophylaxis (PEP) as soon as possible, preferably within 36 h after exposure. Although the need to prescribe antiretroviral postexposure prophylaxis in a timely fashion is common, few data exist regarding the efficacy and optimal regimen for prophylaxis to prevent transmission. Our objectives were to examine the limited human and animal data on postexposure prophylaxis, to elucidate the factors that affect the choice of 2 versus 3 drugs as the optimal prophylactic drug regimen, and to place these findings within a mathematical framework to help guide the prescription of PEP.