BACKGROUND: Obesity has become a major health and economic problem with increasing prevalence. Unfortunately, no country can act as public health exemplar for reduction of obesity. The finding of associations between sedentary behaviors and obesity, independent of the level of physical activity, may offer new insights to prevent this burdensome problem. PURPOSE: To evaluate prospectively the relationship between annual distance traveled by motor vehicles and subsequent incidence of overweight or obesity in a Mediterranean cohort. METHODS: Data from a prospective cohort study (Seguimiento Universidad de Navarra Project, 1999-2011) with a permanently open recruitment were analyzed. Self-administered questionnaires are mailed every 2 years, collecting information on dietary habits, lifestyle, risk factors, and medical conditions. Annual kilometers traveled by motor vehicles were grouped into three categories (≤10,000; >10,000 to ≤20,000; and >20,000). Multivariate Cox regression analyses were used to assess the risk of overweight or obesity across categories of distance traveled annually. RESULTS: In all, 9160 participants (58% female, average age=37 years) were followed up for a median of 6.4 years. During 39,175 person-years of follow-up, 1044 (15.3%) normal-weight participants at baseline became overweight or obese. Among participants who did not change their category of annual kilometers traveled during follow-up, an increased risk of overweight or obesity in the highest category of annual kilometers traveled was observed, compared with the lowest one (hazard ratio=1.4, 95% CI=1.1, 1.7). CONCLUSIONS: This study suggests a potential pernicious effect of the use of motor vehicles on the risk of overweight or obesity.