Obesity is accompanied by altered secretion and disposition of sex and glucocorticoid hormones, including cortisol, and also confounds parameter normalization and drug dosage selection relative to body weight. Prednisolone disposition was assessed in eight obese and four normal male subjects after a dose of 33 mg iv. Steroid concentrations were determined by HPLC. Kinetics were related to ideal body weight (IBW) and total body weight (TBW). Uncorrected steady-state volume of distribution (Vss) of total prednisolone was 20% greater in obese subjects (36.7 and 44.1 l). This effect could be described by the relationship: Vss = 0.54 IBW + 0.09(TBW-IBW), with a distribution coefficient of 0.09 reflecting limited prednisolone uptake by fat. Protein binding parameters and albumin and transcortin concentrations were similar between groups. Uncorrected total and free prednisolone clearances (Cl) were increased in obesity (11.1 and 8.3 l/hr total; 65.4 and 46.5 l/hr free). Free prednisolone Cl correlated strongly (r = 0.80) with degree of obesity expressed as TBW/IBW. In the obese, endogenous cortisol concentrations were initially higher before exogenous steroid dosing, were suppressed at an identical rate, and returned to baseline more slowly than in normal subjects. The apparent hypersensitivity of the adrenal gland offsets the increased Cl of free prednisolone in obesity, indicating that weight-proportional dosage adjustments of this steroid in obesity should reflect TBW.