To determine the relationship between insulin resistance and weight loss in early obesity, we used the euglycemic, hyperinsulinemic clamp to study the effect of a 14-day weight reduction diet in 10 prepubertal and early pubertal obese children (age, 10.1 +/- 1.6 years) on insulin sensitivity. Body weight decreased from 73.7 +/- 6.0 kg to 69.1 +/- 5.8 kg (p < 0.01). Insulin sensitivity before weight reduction negatively correlated with the amount of weight loss during diet (r = -0.8, p < 0.005). Weight loss also positively correlated with height standard deviation score (r = 0.9, p < 0.005). Mean insulin sensitivity increased from 0.068 +/- 0.01 (nmol kg-1 min-1)/(pmol l-1) to 0.096 +/- 0.030 (nmol kg-1 min-1)/(pmol l-1) (p < 0.05, one-tailed test). These results indicate that weight reduction decreases insulin resistance in childhood obesity. The inverse relationship between insulin sensitivity and weight loss during calorie, restriction in these subjects suggests that insulin resistance may enhance weight loss during calorie restriction.