Insulin sensitivity is impaired in type 1 diabetes (T1D) and may be enhanced by islet transplantation, an effect best explained by improved metabolic control. While the minimal model index of insulin sensitivity, S_I, has been used in studies of T1D, it has not before been evaluated against gold-standard measures derived from the euglycemic clamp. We sought to determine how well minimal model S_I derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test compared with total body and peripheral insulin sensitivity estimates derived from the hyperinsulinemic-euglycemic clamp in subjects with T1D and following islet transplantation. Twenty-one T1D subjects were evaluated, including a subgroup (n = 12) studied again after intrahepatic islet transplantation, with results compared with normal controls (n = 11 for the FSIGT). The transplant recipients received 9,648 ± 666 islet equivalents/kg with reduction in HbA_1c from 7.1 ± 0.2 to 5.5 ± 0.1% (P < 0.01) and 10/12 were insulin independent. FSIGT-derived S_I was reduced in T1D pre- compared with posttransplant and with normal [1.76 ± 0.45 vs. 4.21 ± 0.34 vs. 4.45 ± 0.81 × 10⁻⁴(μU/ml)⁻¹·min⁻¹; P < 0.01 for both]. Similarly, clamp-derived total body, and by the isotopic dilution method with [6,6-²H₂]glucose, peripheral insulin sensitivity increased in T1D from pre- to posttransplant (P < 0.05 for both). The predictive power (r²) between volume-corrected S_IC and measures of total and peripheral insulin sensitivity was 0.66 and 0.70, respectively (P < 0.00001 for both). That the minimal model S_IC is highly correlated to the clamp-derived measures indicates that the FSIGT is an appropriate methodology for the determination of insulin sensitivity in T1D and following islet transplantation.