Purpose: Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes (T2D). Whether the degree of insulin resistance predicts adverse outcomes in patients with T2D and acute coronary syndrome (ACS) is uncertain. Methods: The AleCardio trial compared the peroxisome proliferator-activated receptor-α/γ agonist aleglitazar with placebo in patients with T2D and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR, n=4303) or the change in HOMA-IR on assigned study treatment (n=3568) was related to the risk of death or major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter. Results: In unadjusted analysis, two-fold higher baseline HOMA-IR was associated with lower risk of death (HR 0.79, 95% CI 0.68-0.91, p=0.002). Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR 0.99, 95% CI 0.83-1.19, p=0.94). Baseline HOMA-IR was not associated with MACE, nor was the change in HOMA-IR on study treatment associated with death or MACE. Conclusions: After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or MACE in patients with T2D and ACS.