HIV-infected individuals living in or having come from geographic areas endemic for Histoplasma capsulatum are at increased risk of developing a disseminated progressive form of infection (disseminated progressive histoplasmosis or DPH) with this fungus. The degree of immunosuppression, particularly as related to the absolute CD4 T-cell lymphocyte count, correlates to the incidence and severity of disease caused by this endemic fungus. The diagnosis, which relies on culture, histopathology, or radioimmunoassay antigen detection, presents clinical similarities with other opportunistic infection pathogens. Recent published guidelines recommend initial therapy with liposomal amphotericin B, followed by itraconazole, for at least 12 months and perhaps longer. We describe a case of DPH in a newly diagnosed AIDS patient who demonstrated significant clinical, laboratory, and imaging improvement during treatment with trimethoprim-sulfamethoxazole alone. A propos this case, we review DPH and the published literature addressing the effectiveness of trimethoprim-sulfamethoxazole as a treatment option, suggesting its consideration for inclusion in future trials.