Background: Hemophagocytic Syndrome (HPS) is an uncommon disorder with high mortality. HPS is reported to be usually related to some underlying conditions; autoimmune (AI) and hematological malignancies (HM) are two main underlying conditions. Here, we attempted to determine the clinical characteristics/differences of HPS according to underlying conditions; AI vs. HM, based on our experience. Methods: We studied all adult patients with HPS diagnosed at our institution from 2005 to 2019. Demographic, clinical characteristics, laboratory findings, underlying disorders, hospital stay and prognosis variables were examined and related to the underlying conditions. Results: 30 patients (median age of 55 years and male/female of 14/16) met the inclusion criteria which we analyzed: HM: 12 (40%), AI: 10 (33%), and others: 8 (27%). HM group, compared with AI group, showed a significantly longer length hospital stay (HM vs AI: 61.5 vs 30.5 (median)), more severe thrombocytopenia, leukocytopenias, and neutropenia, and importantly, higher mortality (with overall mortality and HM-related HPS-mortality being 43.3 and 66.7%, respectively). Contrarily, HM group, compared with AI group, showed less severe liver abnormalities (AST; 106 vs 457 (median): ALT; 109 vs 457 (median)). Conclusions : The HM subgroup presented a greater mortality and a higher number and severe cytopenias but lower elevation of transaminases.