Rationale: The biological mechanisms linking environmental exposures with cardiovascular disease (CVD) pathobiology are incompletely understood. We sought to identify circulating proteomic signatures of environmental exposures, and examine their associations with cardiometabolic and respiratory disease (CMD) in observational cohort studies. Methods: We tested the relations of >6500 circulating proteins with 29 environmental exposures across the built environment, green space, air pollution, temperature, and social vulnerability indicators in nearly 3000 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study across 4 centers using penalized and ordinary linear regression. In >3500 participants from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS), we evaluated the prospective relations of proteomic signatures of the envirome with CVD and mortality using Cox models.Results: Proteomic signatures of the envirome identified novel/established CVD-relevant pathways including DNA damage, fibrosis, inflammation, and mitochondrial function. The proteomic signatures of the envirome were broadly related to CMD and respiratory phenotypes (e.g., body mass index, lipids, and left ventricular mass) in CARDIA, with replication in FHS/JHS. A proteomic signature of social vulnerability was associated with a composite of CVD/mortality (1428 events; FHS: HR=1.16, 95% CI 1.08-1.24, P=1.77e-05; JHS: HR=1.25 95% CI 1.13-1.38, P=6.38e-06; HR expressed as per 1 standard deviation increase in proteomic signature), robust to adjustment for known clinical risk factors. Conclusions: Environmental exposures are related to an inflammatory-metabolic proteome, which identifies individuals with CMD and respiratory phenotypes and outcomes. Future work examining the dynamic impact of the environment on human cardiometabolic health is warranted.