Objective: To investigate the efficacy of fluconazole prophylaxis against systemic fungal infections in HIV-positive patients. Design: Open label treatment compared with historical controls. Setting: Patients were seen at the Parkland Memorial Hospital HIV Clinic, Dallas, Texas, USA between 1 March 1990 and 28 February 1991. Patients, participants: Three hundred and thirty-seven historical controls were followed for 157 patient-years, and 329 fluconazole-treated patients for 145 patient-years, Interventions: Fluconazole (100 mg daily) was administered to all patients with CD4 lymphocyte counts < 68 x 10(6)/l seen at our HIV clinic after 1 March 1990. Main outcome measures: Lysis-centrifugation blood cultures were recorded monthly for all patients during both study periods. Results: Twenty infections (16 cryptococcosis, four histoplasmosis) occurred in 337 historical reference control patients (product-limit 1-year incidence, 7.5 +/- 2.0/year). Four infections (one cryptococcosis, three histoplasmosis) occurred in the treated patient group (product-limit 1-year incidence, 1.8 +/- 0.9/year). Conclusions: Fluconazole warrants further evaluation for prophylaxis against systemic fungal infections in HIV-positive patients.