Malignant histiocytoses (MH) are rare and poorly understood cancers, with no established therapeutic guidelines. We conducted a national retrospective study of MH diagnosed in France between 2000 and 2023. All cases underwent centralized histological review, and several malignant tumors with a stroma highly enriched in histiocytes were excluded. In total, 141 patients were included, with a median age of 62 years (range, 1-87). The cases comprised either primary MH (64%) or MH associated with other hematologic malignancies (36%). Phenotypes corresponded to histiocytic (43%), interdigitating dendritic cell (37%) or Langerhans cell (12%) sarcomas, or high-grade indeterminate dendritic cell tumors (10%), as per the World Health Organization classification. Tumor cells were almost universally positive for CSF1R and PU.1, and 85% showed phosphorylated extracellular signal-regulated kinase positivity. Next-generation sequencing was performed in 75 cases. Mutations in the MAPK pathway were more frequent in secondary compared with primary MH (90% vs 55%; P = .0012). PTPN11 mutations were exclusively observed in primary MH (P = .0035). Mutations in genes related to DNA methylation mechanisms (TET2, ASXL1, DNMT3A) and TP53 were present in 20% and 14% of cases, respectively. Although therapeutic regimens varied considerably, our results demonstrate that surgical resection in localized cases, and the use of BRAF or MEK inhibitors achieved the highest complete response rates, at 63% and 21%, respectively. The prognosis remains poor, with a 5-year overall survival rate of 31%, which is comparable to that of T/natural killer cell lymphomas. Prospective follow-up and a standardized treatment approach in specialized reference centers are crucial to improving patient survival. This trial was registered at www.clinicaltrials.gov as #NCT04437381.