Habitual physical activity and chronic exercise may positively influence circulating cytokines in youth as in adults. The purpose of this study was to determine if adolescents reporting higher amounts of physical activity had a better cytokine profile independent of weight status. We compared the concentrations of cytokines in highly active (n = 60) and less active adolescents (n = 60) of different weight status [normal weight (BMI < 75th percentile), and overweight (BMI > 95th percentile)]. Vigorous physical activity (VPA) was obtained through a questionnaire and included activities with a MET level of > or =6. Adiponectin, resistin, TNF-alpha and IL-6 were measured in fasting plasma samples. Anovas indicated that girls with high VPA had higher adiponectin than girls with low VPA (P < 0.05), but similar resistin, TNF-alpha and IL-6 concentrations (P > 0.05). Boys with high VPA had only a trend to lower resistin than those with low VPA (P = 0.052). Differences between VPA groups were independent of weight status. In adolescents, higher amounts of accumulated habitual VPA may improve some cytokines, reducing the risk of inflammation associated with increased adiposity and insulin resistance. The effect of physical activity appears to be independent of weight status.