Forty-one cases of histiocytic sarcoma (HS) in C57BL/6J mice were histopathologically studied with special regard to unexpected associated hematopoietic disorders. These cases were retrieved among C57BL/6J female mice used as control mice in a chronic low-dose irradiation experiment. Hematopoietic characteristics were analysed by comparison to 41 disease-free mice from the same cohort. Tumoral involvement of the liver was observed in all 41 HS-bearing mice, followed by infiltration of the spleen (61.8%), lung (32.4%), bone marrow (14.3%), uterus (12.2%), lymph node (9.8%), and kidney (2.4%). By comparative analysis, we were able to demonstrate a significant association of HS with liver hematopoiesis (89.5% in HS group vs 15% in control mice, p < 0.00001), and with central hematopoietic disorders involving the myelocytic cells (decreased in HS, p = 0.003) and erythrocytic cells (increased in HS, p = 0.001). Microscopic characteristics of these 41 cases and physiopathology of the newly described hematopoietic features in HS are further discussed.