The aim of this study was to investigate the association between insulin resistance and physical fitness, leptin concentration, body composition and family history for diabetes in non-selected young children. Physical fitness, fasting plasma glucose, insulin and leptin concentrations, anthropometric characteristics and medical history were available in two hundred and fifty-seven 7-year-old Dutch children. Correlations with the homeostasis model assessment (HOMA) index for insulin resistance were studied. A multiple regression model was calculated for HOMA. The differences between children with or without a family history for diabetes were not significant. Boys scored higher on glucose concentration and aerobic fitness and lower on sum of skin folds and leptin concentration (p<.05). After adjustment for sum of skin folds, HOMA was significantly associated with leptin in both genders (boys r=.184 p=.031; girls r=.430 p=.000). The association between physical fitness and HOMA was mediated by sum of skin folds. The associations were stronger in girls than in boys. In the regression model (R(2)=.205) the leptin concentration was the only significant predictor for HOMA. The influence of family history for diabetes on insulin resistance is shown as a trend at this age. Our findings suggest that plasma leptin concentration is independently associated with the development of insulin resistance in a non-selected prepubertal population. The association of physical fitness with insulin resistance seems to be mediated by the sum of skin folds.