PURPOSE: We aimed to evaluate the relationship of physical activity and obesity with glycemic control and insulin resistance. METHODS: A randomized, population-based, cross-sectional health and nutrition survey was conducted in the province of Athens, Greece. Subjects included 1514 men and 1528 women without evidence of cardiovascular or other chronic disease. Participants were classified as inactive, minimally active, or health-enhancing physical activity (HEPA) active based on the International Physical Activity Questionnaire. Insulin sensitivity was assessed by the homeostatic model (HOMA), and overweight or obesity was assessed according to BMI (BMI >or= 25). Related social, biological, and lifestyle factors were also recorded and used as potential confounders. RESULTS: Five hundred sixty-five (37.3%) men and 493 (32.3%) women were classified as physically active. From the 1058 (34.8%) subjects who were classified as active, 306 (10.1%) met the criteria for HEPA active, and the rest were minimally active. HEPA active and minimally active subjects smoked less and had lower BMI, waist, and waist-to-hip ratio. Lean and overweight or obese subjects with sedentary lifestyle had greater levels of glucose, insulin, and insulin resistance [corrected] However, overweight or obese volunteers with physical activity levels classified as HEPA had similar levels of glucose and insulin sensitivity, with lower insulin than lean inactive individuals. Linear regression analysis between HOMA and physical activity, taking into consideration several social and biological factors, showed that physical activity (MET x min x wk(-1)), age, BMI, and total energy intake are important predictors of HOMA, whereas other factors such as waist circumference did not reach statistical significance. CONCLUSION: Our data show that physical activity is a significant factor on insulin sensitivity, whereas increased physical activity may ameliorate the well-known effects of obesity on insulin sensitivity.