Background: Development of insulin resistance (IR) may be important in the pathogenesis of both metabolic syndrome and type 2 diabetes mellitus. Few data are available regarding the short-term efficacy of the peroxisome proliferator-activated receptor ligand bezafibrate on IR, and its long-term effect is unknown. The present analysis aimed to investigate the effect of bezafibrate on IR in patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention Study. Methods: Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from patients who completed a 2-year, randomized, double-blind, placebo-controlled study. The homeostatic indexes of IR (HOMA-IRs) were calculated according to the homeostasis model of assessment. Results: Both the patients taking bezafibrate (n = 1262) and those taking placebo (n = 1242) displayed similar baseline characteristics. The HOMA-IRs significantly correlated at baseline and during follow-up with glucose (r=0.35 and 0.31, respectively) and triglycerides (r=0.16 and 0.19, respectively). In a subgroup of 351 patients with diabetes, HOMA-IR at baseline was 88% higher than in their counterparts with normal glucose levels (P<.001). In the placebo group, during follow-up there was a significant 34.4% rise in HOMA-IR. In contrast, in the bezafibrate group there was only a nonsignificant 6.6% change in HOMA-IR. The intergroup differences in percentage changes of HOMA-IR were in favor of bezafibrate (P<.001). Conclusions: In patients with coronary artery disease enrolled in our study, as represented by the placebo group, HOMA-IR increased over time. During the 2 years of the follow-up, bezafibrate significantly attenuated this process.