Insulin resistance is a risk factor for colon cancer, but it is not clear which of its metabolic sequelae are involved. The objective of this study was to determine whether increased adiposity and elevated circulating lipids commonly seen in insulin resistance promote colon carcinogenesis independent of changes in insulin. We made use of Muscle-specific Insulin Receptor Knockout (MIRKO) mice that exhibit elevated serum triglycerides (TG), free-fatty acids (FFA) and fat mass, but have similar body weights, circulating glucose and insulin and insulin sensitivity to their wildtype littermates used as controls. Seven-week old male MIRKO mice and controls received 4 weekly i.p. injections of either 5 mg/kg azoxymethane (AOM) to induce aberrant crypt foci (ACF) or 10mg/kg AOM to induce tumors, and were killed at 24 or 40 weeks of age, respectively. The MIRKO mice displayed hyperinsulinemia at 7 weeks of age and reduced insulin sensitivity at 16 weeks of age compared to controls. The previously reported MIRKO phenotype developed between 16 and 24 weeks of age. By 40 weeks of age, however, MIRKO mice were again insulin resistant. ACF development did not differ between MIRKO mice and controls, but MIRKO mice developed significantly fewer colon tumors. Our results suggest that circulating TG and FFA are not promoters of colon tumor development. Indeed, we show that the cumulative effects of the metabolic changes that occur with knock-out of the insulin receptor in muscle are associated with reduced susceptibility to colon tumorigenesis.