Although the minimal-model-based insulin sensitivity index (S1) can be estimated from the results of a simple 180-min intravenous glucose tolerance test (IVGTT), its relationship to widely accepted but technically more difficult clamp-based techniques has not been resolved in humans. Therefore we measured S1 by standard IVGTT, modified IVGTT, and clamp methods in 10 nondiabetic men with %IBW of 109 ± 12 (mean ± SD). In the euglycemic clamp studies, insulin was infused to bring insulin levels (IRI) from basal, 8 ± 4 μU/ml, to plateaus of 21 ± 5 and 35 ± 6 μU/ml. S1[clamp], measured as the increase in glucose (G) clearance per increase in IRI [δINF/(δIRI × G)], averaged 0.29 ± 0.09 ml/kg·min per μU/ml. In the IVGTT studies, 300 mg/kg G was given as an i.v. bolus, and G and IRI were measured for 180 min; in the modified (mod) IVGTT, tolbutamide (300–500 mg) was given i.v. 20 min after the G to observe the effect of an IRI peak on G removal after G level was free of initial “mixing” effects. The S1 estimated by computer did not differ significantly between standard [(6.9 ± 3.4) × 1O−4 min−1 per μU/ml] and modified [(6.7 ± 3.5) × 10−4 min−1 per μU/ml] tests, indicating no bias due to the differing insulin patterns and levels. There was a strong positive correlation between S1 (mod IVGTT) and S1(clamp): r = 0.84; N = 10; P < 0.002. The correlation between S1(standard IVGTT) and S1(clamp) was 0.54, suggesting the modified test is less “noisy” Nonetheless, in eight euglycemic women with a wider range of adiposity, S1(standard IVGTT) has been significantly correlated with %IBW (r = −0.72) and basal IRI (r = −0.84). The correlation between S1 measures by clamp and IVGTT methods provides one step toward validation of the minimal model for studies of insulin action in man.