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Although moderate-to-vigorous physical activity is related to premature mortality, the relationship between sedentary behaviors and mortality has not been fully explored and may represent a different paradigm than that associated with lack of exercise. We prospectively examined sitting time and mortality in a representative sample of 17,013 Canadians 18-90 yr of age.Evaluation of daily sitting time (almost none of the time, one fourth of the time, half of the time, three fourths of the time, almost all of the time), leisure time physical activity, smoking status, and alcohol consumption was conducted at baseline. Participants were followed prospectively for an average of 12.0 yr for the ascertainment of mortality status.There were 1832 deaths (759 of cardiovascular disease (CVD) and 547 of cancer) during 204,732 person-yr of follow-up. After adjustment for potential confounders, there was a progressively higher risk of mortality across higher levels of sitting time from all causes (hazard ratios (HR): 1.00, 1.00, 1.11, 1.36, 1.54; P for trend <0.0001) and CVD (HR:1.00, 1.01, 1.22, 1.47, 1.54; P for trend <0.0001) but not cancer. Similar results were obtained when stratified by sex, age, smoking status, and body mass index. Age-adjusted all-cause mortality rates per 10,000 person-yr of follow-up were 87, 86, 105, 130, and 161 (P for trend <0.0001) in physically inactive participants and 75, 69, 76, 98, 105 (P for trend = 0.008) in active participants across sitting time categories.These data demonstrate a dose-response association between sitting time and mortality from all causes and CVD, independent of leisure time physical activity. In addition to the promotion of moderate-to-vigorous physical activity and a healthy weight, physicians should discourage sitting for extended periods.