Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is considered a rare disease with a high risk of morbidity and mortality. Most research on this disease is conducted in pediatric settings. Therefore, this study aimed to describe the clinical characteristics, laboratory findings, and outcomes related to HLH in people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and disseminated histoplasmosis. Methods A retrospective and descriptive study was conducted in a tertiary hospital in México City from January 2018 to December 2022, including people living with HIV and disseminated histoplasmosis confirmed through direct microbiological or immunological methods with an HScore ≥169 or who met 5 of the 8 HLH-2004 criteria. Results HLH occurred in 36.1% (n = 26) of cases with HIV and disseminated histoplasmosis; the majority were men (84.9%), and their mean age was 30.19 ± 5.6 years. The most frequent clinical manifestations were hepatomegaly (100%), fever (96.2%), and dyspnea (84.6%). The most common biochemical changes were hyperferritinemia (100%), elevated lactate dehydrogenase (100%), and bicytopenia (61.5%). Partial prothrombin time (p = 0.012) and prothrombin time (p = 0.004) were associated with 30-day mortality, and 30-day survival was 65.4%. Conclusions We detected a high frequency of hemophagocytic lymphohistiocytosis; therefore, we encourage physicians to use diagnostic prediction tools (HLH-2004 and HScore criteria) in each reassessment for timely detection.