Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown to impair the actions of insulin on peripheral glucose uptake and suppression of hepatic glucose output (HGO). These studies have been conducted almost exclusively in healthy, lean men. We therefore set out to test the hypothesis that obese subjects, because they are already insulin-resistant, are less susceptible than lean subjects to the inhibitory effects of elevated NEFA on insulin-stimulated glucose disposal. We studied 15 lean (11 men, 4 women; age, 45 [plusmn] 3 years [mean [plusmn] SE]; body mass index [BMI], 22.7 [plusmn] 0.6 kg/m²) and 15 obese normal subjects (11 men, 4 women; 49 [plusmn] 3 years; 31.7 [plusmn] 1.0 kg/m²). Each subject underwent two 5-hour 80-mU/m²/min hyperinsulinemic euglycemic clamps with measurement of glucose kinetics (intravenous 3-³H-glucose). Plasma NEFA levels were elevated in one study for 3 hours before and during the clamp ([sim ]1 mmol/L in both groups) by infusion of 20% Intralipid (60 mL/h) and heparin (900 U/h). The obese subjects had higher fasting insulin levels (9.1 [plusmn] 1.1 v 4.8 [plusmn] 0.6 mU/L, P [lt ] .005) and were insulin-resistant (glucose disposal rate [GDR] at the end of the control glucose clamps: obese, 7.96 [plusmn] 0.55, lean, 10.24 [plusmn] 0.35 mg/kg/min, P [lt ] .002). Contrary to our hypothesis, elevation of plasma NEFA had a similar effect in the lean and obese subjects, both in terms of the absolute reduction of insulin stimulated GDR in the lean (1.82 [plusmn] 0.36 mg/kg/min decrement) and obese subjects (2.03 [plusmn] 0.37 mg/kg/min decrement) and the overall percentage reduction in GDR (lean, 17.1% [plusmn] 3.1%; obese, 24.5% [plusmn] 4.2%; difference not significant [NS]). Suppression of HGO during the lipid clamps was also impaired to a similar extent in the 2 groups. Findings were similar for the 9 obese subjects with a BMI of 30 kg/m² or more. Combining the 2 groups, the NEFA induced reduction of insulin stimulated GDR did not correlate with BMI (r = 0.08, NS) or with insulin sensitivity (GDR) measured in the control study (r = 0.11, NS). In summary, the effect of a short term elevation of plasma NEFA levels on insulin stimulated GDR and suppression of HGO is comparable in lean and moderately obese subjects.