Abstract Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 ± 2.7 years, body mass index 47.1 ± 1) by the euglycemic clamp technique (40 mU/m 2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 ± 2.5 years, body mass index 23 ± 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls ( P < 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg · min −1 of fat free mass was significantly reduced in the massively obese patients compared to the controls ( P < 0.001). Similarly, the M I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients ( P < 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 ± 51 v 467 ± 55 μmol/L, P < 0.05; glycerol 97 ± 9 v 59 ± 11 μmol/L, P < 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups. Alanine, lactate, and 3-hydroxybutyrate displayed similar responses in the massively obese patients and controls during the study. The metabolic clearance rate of insulin (MCR 1) was significantly lower in the massively obese patients compared to the controls when expressed per kg of total body weight but not when calculated per kg of fat free mass. In conclusion, massively obese patients showed marked insulin insensitivity on glucose disposal reflecting primarily muscle insensitivity to insulin action. In contrast to decreased glucose disposal, other metabolic effects of insulin were not markedly impaired. The antilipolytic, antiketogenic, and inhibitory effects on insulin and glucagon production remained essentially intact.