Syngeneic murine colon adenocarcinoma (MCA-38) cells were transplanted in the submucosa of distal colon, proximal colon, cecum, ileum, jejunum, and duodenum of male C57BL/6 mice, with local lymphoid follicles used as points of entry. The tumor grew best at the cecum and led to liver and mesenteric lymph node metastases in 8 and 9 weeks, respectively, after transplantation. Histologically, a local inflammatory reaction involving polymorphonuclear leukocytes was observed within 48–72 hours following transplantation; after this time, the microscopic tumor foci began to grow progressively. Mononuclear lymphoid cells of the gut-associated lymphoid tissue did not infiltrate the progressively growing tumor; however, polymor-phonuclear leukocytes were constantly observed at the tumor periphery in the lamina propria. The studies indicated that orthotopic transplantation as a model system can provide a means of examining the role of the local immune response as a focus of host resistance and as a factor in metastatic tumor spread. The findings also suggested the usefulness of this model in immunotherapeutic and chemotherapeutic studies of secondary hepatic disease.