Histoplasmosis is an important opportunistic infection among HIV-infected patients in endemic areas, and clinical outcomes are often poor. Additional data on factors associated with outcomes are needed to better identify patients who may require aggressive care. Using a cohort of 46 HIV-infected patients with histoplasmosis from an underserved city endemic for histoplasmosis, we explored epidemiology, outcomes, and prognostic factors. Histoplasmosis was the 1st recognized manifestation of HIV infection in 12 (26.1%) of 46 patients. Death occurred in 18 (39%) patients within 3 months of diagnosis of histoplasmosis. Fungemia (odds ratio [OR], 12.1; 95% confidence interval [CI], 1.9-76; P = 0.008), renal insufficiency (OR, 11.3; 95% CI, 1.7-77.2; P = 0.01), and age (OR, 0.9; 95% CI, 0.8-0.98; P = 0.02) were independent predictors of poor prognosis. Histoplasmosis in HIV patients is associated with poor outcomes. Identification of prognostic factors may be helpful in identifying patients who require more aggressive care.