Trimethoprim-sulfamethoxazole (TMP-SMX) is frequently used in human immunodeficiency virus (HIV)-infected patients (HIV+) for treatment or prophylaxis of Pneumocystis carinii pneumonia (PCP). Up to 80% of those patients report adverse reactions to that drug combination. To test the hypothesis that these reactions are immunologically mediated, we quantitated specific IgG and IgE SMX-human serum albumin (HSA) antibodies and immune complexes (IC) in HIV+ patients and in HIV controls. Patients with mild HIV disease had elevated specific SMX-HSA IgG and IC levels compared with those having severe disease or with controls. Conversely, patients with severe HIV disease had statistically elevated levels of specific IgE when compared with patients having milder disease or with controls. There were no differences in either specific antibody or IC levels between patients reporting adverse reactions and those who did not. Results suggest that there are increased levels of SMX-HSA-specific antibodies in some HIV+ patients. The presence of these antibodies appears to be related to severity of disease, rather than clinically significant drug sensitivity.