Leptin has been demonstrated to correlate with body fat content in humans, but the regulation of leptin levels is poorly understood. Therefore, we studied the relation between fasting insulin, plasma leptin, and insulin sensitivity, as assessed by the hyperinsulinemic euglycemic clamp, before and after short term corticosteroid treatment, which is known to induce insulin resistance (3.0 mg dexamethasone, twice daily, for 48 h; total dose, 15 mg) in nine healthy women (mean +/- SE age, 58.6 +/- 0.1 yr; body mass index, 25.9 +/- 1.7 kg/m2). Dexamethasone increased fasting leptin levels by 114 +/- 14% (18.4 +/- 3.3 vs. 39.4 +/- 7.3 ng/ml; P = 0.001) and increased fasting insulin by 51 +/- 12% (P = 0.004). Concomitantly, insulin sensitivity was reduced to 45 +/- 5% (P = 0.001). The increase in leptin correlated with the reduction of insulin sensitivity (r = 0.68; P = 0.044), but this correlation was no longer significant after correction for body mass index. The correlation between the change in plasma leptin and body mass index (r = 0.79; P = 0.012), however, was independent of the change in both fasting insulin and insulin sensitivity. We conclude that short term corticosteroid treatment induces a doubling of fasting leptin in healthy humans. The dexamethasone-induced increase in leptin is dependent of body mass index, but not of insulin levels or insulin sensitivity, which suggests that the influence of dexamethasone on plasma leptin is not mediated by its influences on fasting insulin or insulin sensitivity.