Incidence trends for the 13 most frequent AIDS-defining opportunistic infections (OIs) among men who have sex with men (MSM, n = 15,588) and injecting drug users (IDUs, n = 4475) were examined using data abstracted from medical records in >90 hospitals and clinics in nine US cities during 1991-1996. Among MSM, the most frequent OIs were Mycobacterium avium complex (MAC) disease, Pneumocystis carinii pneumonia (PCP), and cytomegalovirus (CMV) retinitis; decreasing (P < or = .05) trends occurred for 11 OIs (MAC disease, PCP, CMV retinitis, Kaposi's sarcoma, esophageal candidiasis, CMV disease, extrapulmonary cryptococcosis, toxoplasmic encephalitis, tuberculosis, chronic herpes simplex, and disseminated histoplasmosis). Among IDUs, the most frequent OIs were PCP, MAC disease, and esophageal candidiasis; decreasing trends occurred for 5 OIs (PCP, esophageal candidiasis, tuberculosis, chronic herpes simplex, and chronic cryptosporidiosis) and an increase occurred in recurrent pneumonia. The differences in trends for MSM and IDUs may be due to differences in medical care and adherence to preventive medications.