Aberrant crypt foci (ACFs) are putative preneoplastic lesions in the colonic mucosa identified by examining methylene blue-stained whole mounts of colon. ACFs have been previously described in rats treated with genotoxic colon carcinogens. This study determined whether or not a nongenotoxic colon carcinogen could induce ACFs and compared the morphology of these ACFs with those induced by a genotoxic colon carcinogen. Six-wk-old Fischer-344 rats were administered dextran sulfate (DSS, nongenotoxin) in the drinking water or azoxymethane (AOM, genotoxin) by single subcutaneous injection. Rats were sacrificed at 9 and 14 wk after study initiation. Colons were fixed and stained with methylene blue, and the mucosal surface of transilluminated whole mounts was examined with a microscope. The number of ACFs and number of crypts per focus (multiplicity) were recorded. Representative ACFs were processed into glycol methacrylate for hexosaminidase enzyme histochemistry and sections of the remaining colon containing ACFs were embedded in paraffin for morphologic evaluation. In whole mounts, ACFs from AOM- and DSS-treated rats had elongated slit-to-oval-shaped lumens surrounded by a thickened and intensely stained epithelium. DSS-induced aberrant crypts differed from those induced by AOM in that they were frequently larger, tended not to form discrete foci circumscribed by normal crypts, and were located adjacent to ulcers. Total ACFs and large foci (4 or more crypts/focus) were significantly more numerous in AOM-treated rats at both time points. Histologically, DSS-induced ACFs had segmental to diffuse loss of hexosaminidase activity, mucin depletion to increased prominence of goblet cells, and marked distortion of crypt architecture. AOM-induced ACFs had diffuse loss of hexosaminidase activity, variable depletion of mucin, and less distortion of crypt architecture. Variable degrees of epithelial dysplasia were seen in ACFs with both carcinogens, but dysplasia was more severe in DSS-induced ACFs. Colonic mucosal neoplasms were induced by both carcinogens. In subchronic studies, the ACF assay may be a useful method to improve the identification and characterization of xenobiotic-induced changes in colonic mucosal crypts.