Abstract Heart failure (HF) expenditure amounts to several billion per year. Despite advances in medical treatment of HF, mortality after HF onset and rate of recurrent HF decompensation remain high, underscoring an urgent need to identify effective prevention strategies. Observational studies showed a higher risk of death in HF patients with lower levels of vitamin D and two recent post-hoc analyses of trials conducted in mostly post- menopausal women reported a reduction in HF rates in the vitamin D group compared with placebo. Vitamin D has also been reported to improve hemodynamics and left ventricular remodeling in 229 HF patients. However, no randomized trial has examined the effects of vitamin D on primary prevention of HF or on the rate of recurrent HF decompensation in men and women. Efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular events has been reported in trials with low prevalence of stain use only. EPA/DHA can reduce risk factors for HF including myocardial infarction, hypertension, and diabetes. While some but not all observational studies have suggested an inverse association between EPA/DHA and the incidence of HF, no large primary prevention trial of EPA/DHA on HF has been conducted. In addition, effect modification of the effects of EPA/DHA on HF by statin has not been elucidated. This project will investigate the effects of vitamin D and EPA/DHA supplements on the incidence rate of HF and on recurrent HF decompensation in an ancillary study of the VITamin D and OmegA-3 TriaL (VITAL), an NIH-funded randomized controlled trial of 25,874 men and women testing the efficacy of 2,000 IU/day cholecalciferol and 1 g/day EPA/DHA on cardiovascular disease and cancer endpoints.