Background Soluble CD 14 ( sCD 14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD 14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS ( Re asons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case–cohort study, sCD 14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease ( CHD ), and a cohort random sample (n=1039). Cox models estimated hazards ratios ( HR ) of incident ischemic stroke or CHD per 1 SD higher sCD 14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD 14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD 14 was 1.42 (95% CI : 1.12, 1.80), with no association among whites ( HR 1.02 [95% CI : 0.82, 1.27]). Higher sCD 14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD 14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD 14 among blacks at age 45 years was 2.30 (95% CI : 1.45, 3.65) compared with 1.56 (95% CI : 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI : 1.20, 1.91) among blacks and 1.02 (95% CI : 0.80, 1.31) among whites. Conclusions sCD 14 may be a race‐specific stroke and CHD risk marker.