The pathogenesis of spontaneous reticulum cell sarcoma was studied in SJL/J mice. It was found that the neoplasm arose in the mesenteric lymph nodes and in Peyer's patches. The neoplastic reticulum cells grew in clusters that resembled normal germinal centers of lymph nodes. After proliferation, most cells of a neoplastic cluster died. A progression of tissue changes then ensued at the site previously occupied by the neoplastic cells. This began with granuloma formation and ended in dense fibrous tissue. The juxtaposition of clusters of proliferating neoplastic reticulum cells, granulomatous reaction with plasma cells and giant cells, and fibrous scar tissue produced the pleomorphic histologic picture characteristic of reticulum cell sarcoma. Numerous collagen reticulum fibers traversed these tumors. Cytoplasmic folds of tumor cells formed a complex clasping bond around these fibers, suggesting a structural explanation for the observed lack of massive dissemination of tumor cells.