Longitudinal associations between leisure-time physical activity (LTPA) and overall cancer mortality were evaluated within the Third National Health and Nutrition Examination Survey (NHANES III; 1988–2006; n = 15,535). Mortality status was ascertained using the National Death Index. Self-reported LTPA was divided into inactive, regular low-to-moderate and vigorous activity. A frequency-weighted metabolic equivalents (METS/week) variable was also computed. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated for overall cancermortality in the whole sample, by bodymass index categories and insulin resistance

(IR) status. Nonsignificant protective associations were observed for regular low-to-moderate and vigorous activity, and for the highest quartile of METS/week (HRs range: 0.66–0.95). Individuals without IR engaging in regular vigorous activity had a 48% decreased risk of cancer mortality (HR: 0.52; 95% CI: 0.28–0.98) in multivariate analyses. Conversely, nonsignificant positive associations were observed in people with IR. In conclusion, regular vigorous activity may reduce risk of cancer mortality among persons with normal insulin-glucose metabolism in this national sample.