Insulin resistance, through numerous related disturbances in glucose and lipoprotein-lipid metabolism, is associated with an increased risk of ischemic heart disease (IHD). The purpose of the present study was to examine the relationship between increased plasma free fatty acid (FFA) concentrations, as a feature of the insulin resistance syndrome, and the risk of IHD in men. Analyses were carried out in a nested, case-control sample of men selected from a population of 2103 individuals without IHD at baseline among whom 114 developed IHD during a 5-year follow-up period. Incident IHD cases were matched with controls for age, body mass index, smoking habits and alcohol intake. Analyses were performed while excluding (88 cases and 98 controls) and including (103 cases and 99 controls) patients with type 2 diabetes. Among non-diabetic individuals, elevated plasma FFA concentrations (3rd tertile of the distribution) yielded a twofold increase in the risk of IHD (odds ratio [OR] 2.1, P=0.05) compared with lower plasma FFA levels (lowest tertile) after adjusting for non-lipid risk factors. Further adjustment for insulin, triglycerides, apolipoprotein B, HDL cholesterol and small dense LDL attenuated significantly the relationship between plasma FFA concentrations and the risk of IHD. High plasma FFA levels showed no synergism with selected features of the insulin resistance syndrome in determining the risk of IHD. Inclusion of diabetic subjects in the study did not improve FFA independent prognostic value to the risk of IHD. These results suggest that elevated plasma FFA concentrations are associated with an increased risk of IHD. However, a single fasting measurement of plasma FFA levels does not appear to improve our ability to predict IHD onset in men when information on other risk factors is considered.