Colon cancer is the second leading cause of all cancer deaths in the US. Behavioral modifications, such as physical activity (PA) and diet, can effect its prevention and progression. The adenomous polyposis coli (APC) gene is one heritable genetic mutation that can trigger tumor development. To determine if Male and female APCMin+/− mice were randomly assigned to Control, Treadmill, and Activity Wheel groups. Treadmill runners ran on a treadmill at 18 m/min for 60 min, 6 d/wk. Activity wheel runners were housed with 24-h access to voluntary activity wheels. Splenic inflammatory cytokine mRNA levels were analyzed via RT-PCR. We have previously demonstrated that treadmill running can decrease intestinal polyp number and size in male APCMin+/− mice. Splenic IL-6 mRNA concentration decreased 29% in male treadmill runners compared to controls (p=0.036), but not in wheel runners. There was no effect of exercise on female spleen weight or splenic IL-6 mRNA abundance. The crypt depth:villus height ratio in the intestine (CVR), an indirect marker of intestinal inflammation, decreased 21% (p=0.024) and 24% (p=0.029), respectively, in male and female treadmill runners, but not wheel runners. Physical activity-induced attenuation of intestinal polyp number may be related to the systemic and intestinal inflammatory state. Further studies need to examine the interaction between nutraceutical treatments and physical activity on intestinal polyp development.