Heterogeneity in colon tumors implies that environmental, lifestyle, or genetic factors influence the type of mutations seen in tumors. In this study we evaluate the association between previously identified risk factors for colon cancer and Kirsten-ras (Ki-ras) mutations in tumors. The presence of Ki-ras mutations in codons 12 and 13 were determined in a population-based case-control study of colon cancer. Participants were between 30 and 79 years of age at time of diagnosis and include both men and women. Questionnaire data were used to obtain information on lifestyle factors. Valid study data and Ki-ras mutational status were available from 1428 cases of colon cancer, data from 2410 controls were available for comparative purposes. Participants with Ki-ras mutations were more likely to have proximal rather than distal tumors. Cigarette smoking, use of aspirin and/or NSAIDs, use of vitamin/mineral supplements, and consumption of caffeine were associated with both Ki-ras+ and Ki-ras- tumors; the associations were not confounded by dietary intake or other lifestyle factors. Among men, but not among women, those with low levels of physical activity were more likely to have a tumor with a Ki-ras mutation than one without a Ki-ras mutation. However, among women, those with a larger BMI were more likely to have a Ki-ras mutation in their tumor. Given the limited information available on what causes Ki-ras mutations, the information generated from this study indicates that these factors previously associated with colon cancer work through other disease pathways.