Objectives: Histoplasmosis is a systemic mycosis, present globally. We aimed to describe cases of histoplasmosis (Hc) and to establish a risk profile associated with Hc in HIV-infected patients (HIV+). Methods: This was a retrospective study of patients with a clinical laboratory diagnosis of Hc. Data were fed into REDCap, and statistical analysis was performed with R. Results: We included 99 records, 65 HIV+ and 34 HIV−. Average age was 39 years. Median time from onset to diagnosis was 8 weeks in HIV− and 22 weeks in HIV+. Disseminated histoplasmosis occurred in 79.4% of HIV+, vs. 36.4% of HIV− patients. Median CD4 count was 70. Co-infection with tuberculosis was present in 20% of HIV+ patients. Blood cultures were positive in 32.3% of HIV+ vs. 11.8% of HIV−(p = 0.025) patients; bone marrow culture was positive in 36.9% vs. 8.8% (p = 0.003). Most HIV+ patients (71.4%) were hospitalized. On univariate analysis, anemia, leukopenia, intensive care, use of vasopressors and mechanical ventilation were associated with death in HIV+ patients. Conclusions: Most of our patients with histoplasmosis were HIV+, presenting advanced AIDS. Diagnosis was late in HIV+ patients, and they frequently presented disseminated Hc, required hospitalization, and died. Early screening for Hc in HIV+ and drug-induced immunosuppressed patients is crucial.