Progressive disseminated histoplasmosis (PDH) has now been described in acquired immunodeficiency syndrome (AIDS) patients from areas both endemic and nonendemic for histoplasmosis. We review the clinical presentation, diagnosis, and therapy of PDH in patients with AIDS by comparing 64 patients from our series collected retrospectively from Houston and the surrounding area with the case summaries of 61 patients reported in the medical literature. PDH occurred as the first manifestation of AIDS half of the time. Fever, weight loss, enlargement of the liver, spleen, or lymph nodes, and anemia were the most common clinical symptoms and signs. Pulmonary symptoms were less common. The chest roentgenogram showed diffuse interstitial infiltrates in slightly more than half of the patients. Bone marrow biopsy and culture, examination and culture of pulmonary tissue and secretions, and blood culture were the most common initial means of establishing a diagnosis. Ketoconazole alone was ineffective in the majority of cases. Patients treated with amphotericin B (AMB) in a dose of at least 30 mg/kg experienced a significantly longer period of follow-up than those treated with less AMB. However, relapses were observed in four of 16 patients (25%) receiving at least 30 mg/kg of AMB followed by ketoconazole suppression. It appears that long-term suppression with 50 to 100 mg of AMB weekly, after completion of initial therapy, has the best chance of maintaining a satisfactory functional status.