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 to 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 to normal controls (n=11 for the FSIGT). The transplant recipients received 9648±666 islet equivalents/kg with reduction in HbA1c 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 to post-transplant and to normal (1.76±0.45 vs. 4.21±0.34 vs. 4.45 ±0.81 x10^-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 post-transplant (P<0.05 for both). The predictive power (r²) between volume corrected SIC and measures of total and peripheral insulin sensitivity was 0.66 and 0.70 respectively (P<0.00001 for both). That the minimal model SIC 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.