ABSTRACT Recent advances in metabolomics have led to the identification of numerous blood metabolites related to the risk of cardiovascular events. Although these metabolites show great promise as potential novel biomarkers for coronary heart disease (CHD), their relation with coronary risk remains poorly defined due to several knowledge gaps − no prior prospective study has jointly assessed metabolites by taking into account pathways related to biological function; no study has considered changes in metabolite levels over time in relation to subsequent CHD; and research on the dynamic interrelationships of metabolites with traditional CHD risk factors and dietary intakes is limited. The overarching goal of this competing renewal is to fill important gaps in knowledge regarding the metabolomics of CHD, using an exceptionally cost-efficient design that leverages existing resources from three large and well-established U.S. cohorts: the Nurses’ Health Study (NHS), the NHS2, and the VITamin D and OmegA-3 TriaL (VITAL, men and women, ~20% African Americans). Using novel analytical approaches, we propose to develop and validate Metabolomics Risk Scores (MRSs) that incorporate comprehensive metabolite profiling (at overall and pathway levels) for their associations with incident CHD in NHS (700 cases and paired controls) and VITAL (650 cases and paired controls, replication cohort) (Aim 1). Taking advantage of repeated blood collections at two time points approximately 10 years apart in NHS, we will examine whether temporal changes in MRS are related to incident CHD (Aim 2). We will also assess whether biochemical CHD risk factors, and temporal changes in these risk factors, mediate the coronary risk associated with MRS (Aim 3). Finally, using objective dietary data assessed by ‘gold standard’ methods, we will develop Dietary Metabolite Indexes (DMIs) that predict MRS and prospectively analyze relations between temporal changes in DMIs and incident CHD risk (Aim 4). This competing renewal builds upon our long-standing research on risk factors for CHD in the Nurses’ Health Study (research that has resulted in more than 350 publications over the past 34 years) and extends our work to the study of novel metabolomic risk factors. The findings of our proposed project may elucidate new etiologic pathways for atherothrombotic vascular disease, as well as provide novel prevention options and therapeutic strategies for cardiovascular disease. Thus, the proposed study has the potential to have major clinical and public health impact.