Histiocytic sarcoma (HS) is a rare neoplasm that generally behaves aggressively; however, an in-depth study of the clinicopathologic features has not been performed. We explored 23 unique cases of HS occurring as de novo or secondary malignancies. Patients with a secondary HS had lower mean survival by 58.2 months (P =.001). This suggests secondary HSs behave more aggressively than de novo HSs. Introduction: Histiocytic sarcoma (HS) is a rare malignant neoplasm that can occur in patients with a history of treatment for hematologic or solid tumors. Because no optimal treatment has been defined and standardized, the treatment modalities used and outcomes reported have been highly variable. In the present study, 3 major institutions explored the clinicopathologic features of de novo and secondary HS. Materials and Methods: After institutional review board approval, clinical, histopathologic, and immunophenotypic data were collected from patients with a diagnosis of HS and treated at the University of Alabama at Birmingham, University of New Mexico, or Brooke Army Medical Center from January 1, 2003 to December 31, 2016. Results: The databases revealed 23 unique cases of HS. The mean age was 55.4 years (range, 5-84 years) and the male-to-female ratio was 0.92. The mean follow-up period was 89.82 months (range, 14-172 months). Of the 23 patients with HS, 6 had a history of an unrelated malignancy treated with chemotherapy or radiotherapy, with a mean delay of 42.2 months (range, 12-91 months). The mean overall survival during the study period was 54.1 months. The overall survival of those with de novo HS was 70 months compared with 11.8 months for those with secondary HS, with a mean difference of 58.2 months (95% confidence interval, 26.2-90.2 months; P =.001). Conclusion: The shorter overall survival with secondary HS suggests a more aggressive course than that with de novo disease. Larger scale studies are needed to further investigate the biology and genetics of HS.