In disease-endemic areas, histoplasmosis is the main differential diagnosis for tuberculosis among human immunodeficiency virus (HIV)–infected patients. However, no study has compared the two diseases. Thus, the objective of this study was to compare tuberculosis and histoplasmosis in HIV-infected patients. A population of 205 HIV-infected patients (99 with tuberculosis and 106 with histoplasmosis) hospitalized in Cayenne, French Guiana during January 1, 1997–December 31, 2008 were selected retrospectively from the French Hospital Database on HIV. Multivariate analysis showed that tuberculosis was associated with cough (adjusted odds ratio [AOR]= 0.20, 95% confidence interval [CI]= 0.05–0.73) and a C-reactive protein level> 70 mg/L (AOR= 0.98, 95% CI= 0.97–0.99). Variables associated with disseminated histoplasmosis were a γ-glutamyl transferase level> 72 IU/L (AOR= 4.99, 95% CI= 1.31–18.99), origin from French Guiana (AOR= 5.20, 95% CI= 1.30–20.73), disseminated localization (AOR= 6.40, 95% CI= 1.44–28.45), a concomitant opportunistic infection (AOR= 6.71, 95% CI= 1.50–29.96), a neutrophil count< 2,750 cells/mm 3 (AOR= 10.54, 95% CI= 2.83–39.24), a CD4 cell count< 60 cells/mm 3 (AOR= 11.62, 95% CI= 2.30–58.63), and a platelet count< 150,000/mm 3 (AOR= 19.20, 95% CI= 3.35–110.14). Tuberculosis and histoplasmosis have similarities, but some factors show a greater association with one of these diseases. Thus, adapted therapeutic choices can be made by using simple clinical and paraclinical criteria.