BACKGROUND: Colon cancer patients have inferior overall survival than a matched general population (MGP). It is unknown if physical activity is associated with a reduction in this survival disparity. METHODS: Data were analyzed from two National Cancer Institute-sponsored postoperative treatment trials in stage III colon cancer, Cancer and Leukemia Group B (CALGB) 89803 and 80702, with 2876 patients who self-reported physical activity. Physical activity was converted to metabolic equivalents (MET-hours/week). The MGP was derived from the National Center for Health Statistics and matched on age, sex, and year. RESULTS: In CALGB 89803, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET-hours/week had subsequent 3-year overall survival rates that were -17.1% (95% confidence interval [CI], -22.4 to -11.8) and -3.5% (95% CI, -7.7 to 0.3) lower than MGP, respectively. In CALGB 80702, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET-hours/week had subsequent 3-year overall survival rates that were -10.8% (95% CI, -15.4 to -6.9) and -4.4% (95% CI, -7.6 to -1.6) lower than MGP, respectively. In pooled analyses, among patients who were alive and did not have tumor recurrence by year 3 (n = 1908), those with <3.0 and ≥18.0 MET-hours/week had subsequent 3-year overall survival rates that were -3.1% (95% CI, -6.2 to -0.3) lower and 2.9% (95% CI, 1.5-4.2) higher than MGP, respectively. CONCLUSIONS: Physical activity is associated with an attenuation of the survival disparity between patients with stage III colon cancer participating in clinical trials and MGP. Colon cancer survivors who are physically active may achieve survival that approximates the MGP.