OBJECTIVE: To evaluate the cardiovascular (CV) prognostic value of adipokines in a large prospective cohort of patients participating in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. PATIENTS AND METHODS: The effects of the adipokine levels at baseline and change from baseline on the composite outcome (CV death, myocardial infarction, and stroke) were analyzed using unadjusted and fully adjusted Cox models in 2330 patients with type 2 diabetes and coronary artery disease who had participated in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (from January 1, 2001, through December 1, 2008). RESULTS: In a fully adjusted model, baseline leptin and change from baseline leptin were protective for CV events, whereas baseline adiponectin, baseline tumor necrosis factor α (TNF-α), change from baseline TNF-α, baseline C-reactive protein (CRP), and change from baseline CRP were harmful. The effect of baseline leptin on CV events depended on the body mass index (BMI), such that the hazard ratios (HRs) varied between 0.6 and 1.4 across the BMI quintiles (interaction P=.03). The same was true for baseline adiponectin (HR varied from 0.7 to 1.7; interaction P=.01), change from baseline monocyte chemoattractant protein-1 (HR varied from 0.8 to 1.8; interaction P=.03), change from baseline TNF-α (HR varied from 0.9 to 1.4; interaction P=.02), and change from baseline IL-6 (HR varied from 0.7 to 1.8; interaction P=.005). CONCLUSION: Adipokines are independent predictors of CV events in patients with type 2 diabetes and coronary artery disease. The association between the specific adipokines and CV outcome varies depending on BMI. This reflects the complex pathophysiology of CV disease in obesity and may help explain the "obesity paradox." TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006305.