Insulin resistance early after acute myocardial infarction is associated with increased heart failure and mortality. OMEGA-REMODEL was a prospective double-blind 1:1 randomized control trial of patients with AMI. We reported that 6-month treatment with omega-3 fatty acid (O-3FA) 4 g/day attenuated cardiac remodeling accompanied by reduction in inflammation. We hypothesized that insulin resistance modifies the therapeutic effect of O-3FA on post-MI cardiac remodeling. The OMEGA-REMODEL study group was dichotomized according to cohort- and gender-specific median cutoff value of leptin-to-adiponectin ratio (LAR) at baseline (LAR-Hi vs LAR-Lo). Mixed model regression analyses were used to evaluate effect modification of O-3FA on reduction of left ventricular end-systolic volume index (LVESVI) by LAR status. Baseline LAR was evaluated on 325 patients (59 ± 11 years, 81% male). A total of 168 patients were categorized in LAR-Lo, and 157 in LAR-Hi. O-3FA treatment resulted in significant LVESVI reduction in patients with LAR-Lo but not with LAR-Hi (p = 0.0002 vs 0.66, respectively). Mixed model regression analysis showed significant modification of LAR on O-3FA's treatment effect in attenuating LVESVI (p = 0.021). In conclusion, this post-hoc efficacy analysis suggests that LAR status significantly modified O-3FA's treatment effect in attenuating cardiac remodeling. During the convalescent phase of acute infarct healing, patients with lower insulin resistance estimated by LAR appear to derive more therapeutic response from O-3FA toward improvement of LVESVI.