This study was performed to explore further the association between insulin resistance and plasma remnant lipoprotein (RLP) concentration. For this purpose we used the sum of the plasma insulin concentrations before and 30, 60, 90, 120, and 180 min after a 75-g oral glucose load (sigmaIRI) as a surrogate measure of insulin resistance in 61 subjects with impaired glucose tolerance. SigmaIRI was determined on 2 occasions, before and 16 weeks after initiation of a diet and exercise program. At baseline, sigmaIRI correlated with the sum of the plasma glucose concentrations in response to the 75-g oral glucose load (r = 0.26; P < 0.04) as well as plasma concentrations of triglyceride (r = 0.21; P = 0.09), RLP-cholesterol (r = 0.41; P < 0.001), and RLP-triglyceride (r = 0.46; P < 0.001). In contrast, neither total (r = 0.07) nor high density lipoprotein (HDL) cholesterol (r = 0.04) concentrations correlated with sigmaIRI. SigmaIRI was lower in 42 subjects following life-style intervention, associated with significant (P < 0.005) reductions in sigmaglucose, and fasting glucose, insulin, triglyceride, RLP-cholesterol, and RLP-triglyceride concentrations. However, none of these variables decreased in the 19 subjects whose sigmaIRI did not fall. Finally, the change in sigmaIRI following intervention with diet and exercise was significantly associated with differences in sigmaglucose (r = 0.63; P < 0.001) and fasting glucose (r = 0.26; P < 0.05), insulin (r = 0.79; P < 0.001), triglyceride (r = 0.29; P < 0.03), RLP-cholesterol (r = 0.71; P < 0.001), and RLP-triglyceride (r = 0.49; P < 0.001) concentrations. These results demonstrate that variations in concentrations of RLPs are highly correlated with changes in sigmaIRI, consistent with the possibilities that 1) RLP measurements are useful estimates of insulin resistance; and 2) an increase in RLP concentrations may provide the mechanistic link between insulin resistance and coronary heart disease.