Importance  Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood.

Objective  To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking.

Design, Setting, and Participants  We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015.

Exposures  Leisure-time physical activity of a moderate to vigorous intensity.

Main Outcomes and Measures  Incident cancer during follow-up.

Results  A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR 0.58, 95% CI 0.37-0.89), liver (HR 0.73, 95% CI 0.55-0.98), lung (HR 0.74, 95% CI 0.71-0.77), kidney (HR 0.77, 95% CI 0.70-0.85), gastric cardia (HR 0.78, 95% CI 0.64-0.95), endometrial (HR 0.79, 95% CI 0.68-0.92), myeloid leukemia (HR 0.80, 95% CI 0.70-0.92), myeloma (HR 0.83, 95% CI 0.72-0.95), colon (HR 0.84, 95% CI 0.77-0.91), head and neck (HR 0.85, 95% CI 0.78-0.93), rectal (HR 0.87, 95% CI 0.80-0.95), bladder (HR 0.87, 95% CI 0.82-0.92), and breast (HR 0.90, 95% CI 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR 1.27, 95% CI 1.16-1.40) and prostate cancer (HR 1.05, 95% CI 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers.

Conclusions and Relevance  Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.