Background: Research suggests significant health differences between rural dwelling youth and their urban counterparts with relation to cardiovascular risk factors. This study was conducted to (1) determine relationships between physical activity and markers of metabolic syndrome, and (2) to explore factors relating to physical activity in a diverse sample of rural youth. Methods: Data were collected from 4th, 6th, 8th, and 11th grade public school students in the rural Southeastern United States in the spring of 2002. Physiological data included anthropometrics, fasting glucose, lipids, hemodynamics, and skinfold measurements. Psychosocial data included parental support for physical activity, accessibility of physical activity facilities, and safety concerns for physical activity. Behavioral data included self-reported physical activity and sedentary behaviors. Results: After adjusting for sex, race, and age, subjects with low level of physical activity were 3 times more likely to be positive for metabolic syndrome compared to those reporting a high level of physical activity. Subjects reporting a low level of physical activity were 2.4 times more likely to be overweight compared to subjects reporting a high level of physical activity. Students with high levels of physical activity were more likely to have parents who provided money for physical activity lessons and sports teams. Conclusions: Rural youth with low levels of physical activity participation were at increased risks for metabolic syndrome and overweight. Effective physical activity promotions addressing supports for physical activity are urgently needed in rural America.