Histoplasmosis is a common cause of systemic mycosis in areas of the United States where it is endemic. Central nervous system and genitourinary histoplasmosis is rare, especially in immunocompetent hosts. We describe a case of disseminated histoplasmosis in a normal host that was associated with cerebral and prostatic histoplasmosis presenting as fever of undetermined origin, weight loss, and severe debilitating altered mental status. The patient subsequently developed acute renal failure that manifested as obstructive uropathy during antifungal therapy with amphotericin B. Transurethral resection of the prostate resulted in improved renal function during continuation of amphotericin B therapy. Pathological analysis of the prostate revealed necrotizing granulomas with intralesional fungal organisms. Blood and urine cultures were positive for Histoplasma capsulatum. Diagnostic issues and management are discussed. Treatment resulted in return of normal cognitive and motor function. This case is compared with the 8 previously reported cases of H. capsulatum prostatitis.