In the wake of recent breakthroughs in antiviral therapies and Centers for Disease Control and Prevention (CDC) recommendations advocating occupational postexposure prophylaxis (PEP), health care workers are increasingly receiving inquiries about PEP following exposures to the human immunodeficiency virus (HIV) through sex and injection drug use. The probability of HIV transmission by certain sexual or injection drug exposures is of the same order of magnitude as percutaneous occupational exposures for which the CDC recommends PEP. In such cases, if the exposure is sporadic, it seems appropriate to extrapolate from the data on occupational PEP and recommend prophylaxis. However, for individuals with continuing or low-risk exposures, we instead recommend referrals to state-of-the-art risk reduction programs. Clinicians, using local HIV seroprevalence data and their knowledge of transmission probabilities, can help exposed patients make an informed decision regarding PEP. Because of the large number of risky encounters that will not be treated prophylactically, even after significant outreach efforts, public health interventions that emphasize PEP as part of a comprehensive HIV prevention program should be confined to cities with highest HIV prevalences.