Exposure to human immunodeficiency virus (HIV) can occur in a number of situations unique to, or more common among, children and adolescents. Guidelines for postexposure prophylaxis (PEP) for occupational and nonoccupational (eg, sexual, needle-sharing) exposures to HIV have been published by the US Public Health Service, but they do not directly address nonoccupational HIV exposures unique to children (such as accidental exposure to human milk from a woman infected with HIV or a puncture wound from a discarded needle on a playground), and they do not provide antiretroviral drug information relevant to PEP in children. This clinical report reviews issues of potential exposure of children and adolescents to HIV and gives recommendations for PEP in those situations. The risk of HIV transmission from nonoccupational, nonperinatal exposure is generally low. Transmission risk is modified by factors related to the source and extent of exposure. Determination of the HIV infection status of the exposure source may not be possible, and data on transmission risk by exposure type may not exist. Except in the setting of perinatal transmission, no studies have demonstrated the safety and efficacy of postexposure use of antiretroviral drugs for the prevention of HIV transmission in nonoccupational settings. Antiretroviral therapy used for PEP is associated with significant toxicity. The decision to initiate prophylaxis needs to be made in consultation with the patient, the family, and a clinician with experience in treatment of persons with HIV infection. If instituted, therapy should be started as soon as possible after an exposure-no later than 72 hours-and continued for 28 days. Many clinicians would use 3 drugs for PEP regimens, although 2 drugs may be considered in certain circumstances. Instruction for avoiding secondary transmission should be given. Careful follow-up is needed for psychologic support, encouragement of medication adherence, toxicity monitoring, and serial HIV antibody testing.