We investigated the histologic phenotype of experimentally induced colonic tumors in 412 rats: 300 Sprague-Dawley rats (treated with dimethylhydrazine = DMH) and 112 F-344 rats (treated with glutamic acid pyrolysate = Glu). Of the 300 DMH-treated Sprague-Dawley rats, 278 (92.6%) developed a total of 358 colonic tumors: 60 adenomas and 298 invasive adenocarcinomas. Of the 60 adenomas, 45 (75.0%) were exophytic adenomas and the remaining 15 (25.0%) were flat adenomas. Of the 298 adenocarcinomas, 82 (27.5%) were exophytic adenocarcinomas arising in exophytic adenomas, 39 (13%) were flat adenocarcinomas originating in flat adenomas (n = 38) or intramucosal (n = 1), 90 (30.2%) were lymphoid-associated adenocarcinomas (LAC), arising in lymphoid-associated mucosa, and the remaining 87 (29.2%) were overt adenocarcinomas (usually signet-ring cell type carcinomas). In contrast, among the 112 Glu-treated F-144 rats, 62 (55.3%) developed a total of 63 colonic tumors: 52 adenomas and 11 adenocarcinomas. All 52 adenomas were exophytic adenomas and all 11 adenocarcinomas were exophytic tumors originating in exophytic adenomas. No flat neoplastic lesions or LAC were found. Glu-tumors were located predominantly in the cecum and in the right colon and were either tubular adenomas or tubular adenocarcinomas. In contrast, the tumors in the cecum and in the right colon in DMH-treated rats were usually LAC of signet-ring cell type. Neither flat adenomatous lesions (flat adenomas or flat adenocarcinomas) nor LAC were recorded in F-344 rats treated with Glu. The colonic adenomas found in the F-344 rats attained a huge size (when compared with those seen in DMH-treated rats). While the cause(s) of the difference in the histologic phenotypes and their localization as well as of the difference in the size of the tumors between the two experimental groups remains unclear, it is conceivable that Glu binds, mutates, suppresses, or interacts with oncogenes in colonic epithelial cells in a different fashion than DMH. A review of the literature indicates that the genetic differences in the two strains of rats used in the present work may not account for the difference in the results obtained.