BACKGROUND: Monocytes/macrophages participate in cardiovascular disease. CD163 (cluster of differentiation 163) is a mono-cyte/macrophage receptor, and the shed sCD163 (soluble CD163) reflects monocyte/macrophage activation. We examined the association of sCD163 with incident cardiovascular disease events and performed a genome-wide association study to identify sCD163-associated variants. METHODS AND RESULTS: We measured plasma sCD163 in 5214 adults (aged ≥65 years, 58.7% women, 16.2% Black) of the CHS (Cardiovascular Health Study). We used Cox regression models (associations of sCD163 with incident events and mor-tality); median follow-up was 26 years. Genome-wide association study analyses were stratified on race. Adjusted for age, sex, and race and ethnicity, sCD163 levels were associated with all-cause mortality (hazard ratio [HR], 1.08 [95% CI, 1.04– 1.12] per SD increase), cardiovascular disease mortality (HR, 1.15 [95% CI, 1.09–1.21]), incident coronary heart disease (HR, 1.10 [95% CI, 1.04–1.16]), and incident heart failure (HR, 1.18 [95% CI, 1.12–1.25]). When further adjusted (eg, cardiovascular disease risk factors), only incident coronary heart disease lost significance. In European American individuals, genome-wide association studies identified 38 variants on chromosome 2 near MGAT5 (top result rs62165726, P=3.3×10⁻¹⁸),19 variants near chromosome 17 gene ASGR1 (rs55714927, P=1.5×10⁻¹⁴), and 18 variants near chromosome 11 gene ST3GAL4. These regions replicated in the European ancestry ADDITION-PRO cohort, a longitudinal cohort study nested in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment Intensive Treatment In peOple with screeNdetcted Diabetes in Primary Care. In Black individuals, we identified 9 variants on chromosome 6 (rs3129781 P=7.1×10⁻⁹) in the HLA region, and 3 variants (rs115391969 P=4.3×10⁻⁸) near the chromosome 16 gene MYLK3_. CONCLUSIONS: Monocyte function, as measured by sCD163, may be predictive of overall and cardiovascular-specific mortality and incident heart failure.