Objective-To investigate the relationship of body weight and its changes over time with physical activity.Design-Population-based prospective cohort study (Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition, EPIC-Norfolk, United Kingdom) Subjects-25639 men and women aged 39-79 years at baseline. Physical activity was selfreported. Weight and height were measured by standard clinical procedures at baseline and selfreported at 18-month and 10-y follow-ups (calibrated against clinical measures). Main outcome measure was physical activity at the 10-y follow-upResults-Body weight and physical activity were inversely associated in cross-sectional analyses. In longitudinal analyses, an increase in weight was associated with higher risk of being inactive 10 years later, after adjusting for baseline activity, 18-month activity, sex, baseline age, prevalent diseases, socioeconomic status, education, smoking, total daily energy intake, and alcohol intake. Compared with stable weight, a gain in weight of >2 kg/y during short-, mediumand long-term was consistently and significantly associated with greater likelihood of physical inactivity after 10 y, with the most pronounced effect for long-term weight gain, OR=1.89 (95% CI: 1.30-2.70) in fully adjusted analysis. Weight gain of 0.5-2 kg/y over long term was substantially associated with physical inactivity after full adjustment, OR=1.26 (95% CI: 1.11-1.41).Conclusion-Weight gain (during short-, medium-and long-term) is a significant determinant of future physical inactivity independent of baseline weight and activity. Compared with maintaining weight, moderate (0.5-2 kg/y) and large weight gain (>2 kg/y) significantly predict future inactivity; a potentially vicious cycle including further weight gain, obesity and complications associated with a sedentary lifestyle. Based on current predictions of obesity trends, we estimate that the prevalence of inactivity in England would exceed 60% in year 2020.