The Disposition Index, the product of the insulin sensitivity index (SI) and the acute insulin response to glucose, is linked in African-Americans to chromosome 11q. This link was determined with SI calculated with the nonlinear regression approach to the minimal model and data from the Reduced-Sampled-Insulin-Modified-Frequently-Sampled-Intravenous-Glucose-Tolerance-Test (Reduced-Sample-IM-FSIGT). However, the application of the nonlinear regression approach to calculate SI using data from the Reduced-Sample-IM-FSIGT has been challenged as being not only inaccurate but also having a high failure rate in insulin-resistant subjects. Our goal was to determine the accuracy and failure rate of the Reduced-Sample-IM-FSIGT using the nonlinear regression approach to the minimal model. With SI from the Full-Sample-IM-FISGT considered the standard and using the nonlinear regression approach to the minimal model, we compared the agreement between SI from the Full and Reduced-Sample-IM-FSIGT protocols. One hundred African-Americans, (BMI 31.3±7.6 kg/m2 (mean±SD), range 19.0-56.9 kg/m2) had FSIGTs. Glucose (0.3g/kg) was given at baseline. Insulin was infused from 20 to 25 minutes (total insulin dose 0.02U/kg). For the Full-Sample-IM-FSIGT, SI was calculated based on the glucose and insulin samples taken at -1, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 180. For the Reduced-Sample-FSIGT, SI was calculated based on the timepoints which appear in bold. Agreement was determined by Spearman correlation, concordance and the Bland-Altman method. In addition, for both protocols, the population was divided into tertiles of SI. Insulin resistance was defined by the lowest tertile of SI from the Full-Sample-IM-FSIGT. The distribution of subjects across tertiles was compared by rank order and kappa statistic. We found that the rate of failure of resolution of SI by the Reduced-Sample-IM-FSIGT was 3%(3/100). For the remaining 97 subjects, SI for the Full and Reduced-Sample-IM-FSIGT were: 3.76±2.41 L.mU-1.min-1, range 0.58-14.50 and 4.29±2.89 L.mU-1.min-1, range 0.52-14.42, relative error 21±18%, Spearman r=0.97, concordance 0.94, (both P<0.001). After log transformation the Bland Altman limits of agreement were: -0.29 and 0.53. The exact agreement for distribution of the population in the insulin-resistant tertile versus the insulin-sensitive tertiles was 92%, kappa 0.82±0.06. Using the nonlinear regression approach and data from the Reduced-Sample-IM-FSIGT in subjects with a wide range of insulin sensitivity, failure to resolve SI occurred in only 3% of subjects. The agreement and maintenance of rank order of SI between protocols supports the use of the nonlinear regression approach to the minimal model and the Reduced-Sample-IM-FSIGT in clinical studies.