We wished to determine the extent to which drugs used to treat HIV disease and its clinical manifestations are prescribed for conditions other than those listed on the U.S. Food and Drug Administration's approved drug label, how such “off-label” use varies by patient characteristics and type of HIV-related medical condition, and the extent to which physicians alter the way they treat HIV-related conditions because of reimbursement problems associated with off-label drug use. We surveyed 1,530 primary care providers for people with HIV disease between February and May 1993. A three-part survey instrument was used to obtain data on the drugs prescribed for the last three patients with HIV disease treated by the provider, the preferred choice of therapy for 32 specific HIV-related conditions, and the extent to which providers faced reimbursement problems regarding the use of drugs for off-label indications. Three drug compendia were used as cited sources of off-label drug uses. In all, 387 (32%) evaluable surveys were returned, yielding data on 1,148 patients. The majority (81%) of patients received at least one drug off-label, and almost half (40%) of all reported drug therapy was off-label. Most off-label drug use was for treatment and prevention of HIV-related opportunistic infections, which frequently represented the community standard of practice (e.g., trimethoprim/sulfamethoxazole for prevention of Pneumocystis carinii pneumonia), or the de facto standard of practice when no licensed therapies were available (e.g., drugs for treatment of Mycobacterium avium complex, MAC). More than 75% of off-label usage was cited in at least one of the three authoritative medical compendia. The use of drugs for off-label indications in HIV care is common and frequently represents community standards of care. Reliance on drug compendia for support of off-label drug use accounts for the majority of such uses, although many legitimate off-label uses may not be included because of compendia publication lag. The prevalence of off-label drug use in routine clinical practice and the development of newer and more costly drugs for treatment of HIV and its medical complications argues for the articulation of an explicit national reimbursement policy for off-label uses of prescription drugs so that medically appropriate therapies will be available to those with insurance in a rational, consistent way.