Histiocytic sarcoma (HS) spontaneously arises in the liver in mice ; however, the cellular origins of hepatic HS have not been fully clarified. In this study, we immunohistochemically analyzed 18 cases of hepatic HS from the archives of our previous experiments. In all cases, the tumor cells showed positive reactions for the macrophage-specific markers F4/80 and CD68. The cells were negative for mesenchymal cell and lymphoid cell markers, suggesting that germ cell tumor or lymphoma components do not coexist in the neoplasm. We detected scattered Ly6C(+)F4/80(-) macrophage precursors in the extramedullary hematopoietic foci and liver tissue around the HS lesions. We also showed that certain populations of HS cells express the Ly-6C antigen. These findings suggest that Ly-6C(+) macrophage progenitor cells are a possible cellular origin of murine hepatic HS. Our study identified a novel phenotype of murine HS in two of 18 cases. These cases showed the nodular accumulations of tumor cells with cohesive cytoplasm mimicking the features of epithelioid granuloma. In agreement with the expression of CD204 in epithelioid cells in granulomatous diseases, these HS cells hardly expressed CD204, although the common type HS cells were strongly positive for this antigen. These data suggest that hepatic HS may stem from Ly-6C(+) macrophage precursors. Furthermore, a subset of hepatic HS cases can possibly differentiate into epithelioid cell-like phenotypes.