Clinically apparent involvement of the central nervous system is a rare event in cases of disseminated histoplasmosis, even in HIV-infected persons. Despite therapy with amphotericin B, mortality remains very high. Reported here is the case of an HIV-infected patient with a 3-month history of fever, cough, weight loss and miliary lung infiltrates. Four weeks after initiation of tuberculostatic therapy, high-grade fever, neurological symptoms, personality changes and respiratory deterioration occurred. Magnetic resonance imaging of the brain showed multiple mass lesions, and a chest radiograph revealed worsening of pulmonary infiltrates. Methenamine silver staining of a lung biopsy specimen demonstrated Histoplasma capsulatum. Subsequently, this pathogen was cultured from lavage fluid. Following high-dose intravenous fluconazole therapy (800 mg once daily), the patient's condition improved markedly within 10 days, followed by an almost complete resolution of pulmonary and cerebral mass lesions. This is believed to be the first documented case of rapid improvement of disseminated histoplasmosis with central nervous system involvement in an HIV-infected patient upon induction of therapy with fluconazole.