The important role of chemoprophylaxis for the prevention of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus type 1 (HIV)-infected patients is undisputed. The most cost-effective regimen, however, is unknown. We reviewed our experience at two hospitals in the New York City area in which low-dose, intermittent therapy with the combination of trimethoprim and sulfamethoxazole was used to prevent PCP in HIV-infected patients. During a total of 202 months of primary prophylaxis in 32 patients and 319 months of secondary prophylaxis in 35 patients, PCP was diagnosed only once. More than 80% of patients were receiving zidovudine concomitantly. Adverse reactions to trimethoprim-sulfamethoxazole occurred in 31% and 52% of those receiving primary or secondary prophylaxis, respectively. When those patients who were considered ineligible to receive trimethoprim-sulfamethoxazole prophylaxis (principally based on a prior adverse drug reaction) are also factored in, then approximately 50% of HIV-infected patients are candidates for long-term trimethoprim-sulfamethoxazole prophylaxis. The projected cost savings of this prophylaxis regimen, compared with those currently recommended by the US Public Health Service, are enormous.