Drug hypersensitivity reactions are often observed by clinicians treating patients infected with the human immunodeficiency virus (HIV). For certain drugs, the incidence of these reactions appears to be higher than previously reported in the general population. The best example is trimethoprim-sulfamethoxazole, associated with rash, fever, hematologic disturbances, transaminase elevation, and, less frequently, more severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylactic-like reactions. Other sulfa congeners, pentamidine, antituberculosis regimens containing isoniazid and rifampin, amoxicillin-clavulanate, clindamycin, and thalidomide also have been associated with an increased incidence of adverse reactions, some of which could involve allergic mechanisms. Effective dosage and management strategies are needed to prevent or ameliorate hypersensitivity reactions when they occur.