Repetitive treatment with the organotropic colon carcinogen, 1,2-dimethylhydrazine (DMH), produces tumors in susceptible mouse strains that exhibit pathological features associated with the human disease. As in human populations, the genetic background of laboratory animals comprises a significant component to this organ-specific carcinogenesis, and several mouse lines, including AKR/J and DBA/2J are highly resistant to the tumorigenic effects of DMH. During the course of ongoing studies to establish phenotypic differences between susceptible (SWR/J and P/J) and resistant strains, we have examined the colonic mucosa of DMH-treated mice for the presence of aberrant crypt foci (ACF). ACF represent an early morphological lesion in stepwise progression of colon cancer. In Experiment 1, 6-week-old SWR/J and AKR/J mice were injected with DMH (35 and 20 mg/kg, respectively) once a week for 2 weeks. Five weeks later, colons were removed and ACF visualized at low magnification by light microscopy after methylene blue-staining. Only SWR/J mice revealed focal atypia indicative of preneoplastic change. To obtain additional information about their morphology, tissue sections containing ACF were sectioned and stained with H&E. ACF are larger and have a thicker epithelial lining than normal crypts. H&E confirmed the absence of these lesions in untreated SWR/J and DMH-exposed AKR/J mice. In Experiment 2, SWR/J and DBA/2J mice were injected with DMH (35 mg/kg) once a week for 2 weeks. Nine weeks later, colons were analyzed for ACF formation. Comparable to the first experiment, no ACF were observed in the colonic mucosa of the resistant DBA/2J line. In contrast, ACF were readily identified in the middle and distal colons of similarly exposed SWR/J mice. This differential response between resistant and susceptible mouse lines further supports an important role for ACF in the stepwise progression of colon cancer.