To determine factors that explain the higher Black:White cardiovascular disease (CVD) mortality rates among US adults. We analyzed data from the Reasons for Geographic and Racial Differences in Stroke study from 2003 to 2017 to estimate Black:White hazard ratios (HRs) for CVD mortality within subgroups younger than 65 years and aged 65 years or older. Among 29 054 participants, 41.0% who were Black and 54.9% who were women, 1549 CVD deaths occurred. Among participants younger than 65 years, the demographic-adjusted Black:White CVD mortality HR was 2.23 (95% confidence interval [CI] = 1.87, 2.65) and 1.21 (95% CI = 1.00, 1.47) after full adjustment. Among participants aged 65 years or older, the demographic-adjusted Black:White CVD mortality HR was 1.58 (95% CI = 1.39, 1.79) and 1.12 (95% CI = 0.97, 1.29) after full adjustment. When we used mediation analysis, socioeconomic status explained 21.2% (95% CI = 13.6%, 31.4%) and 38.0% (95% CI = 20.9%, 61.7%) of the Black:White CVD mortality risk difference among participants younger than 65 years and aged 65 years or older, respectively. CVD risk factors explained 56.6% (95% CI = 42.0%, 77.2%) and 41.3% (95% CI = 22.9%, 65.3%) of the Black:White CVD mortality difference for participants younger than 65 years and aged 65 years or older, respectively. The higher Black:White CVD mortality risk is primarily explained by racial differences in socioeconomic status and CVD risk factors. (. Published online ahead of print March 19, 2020: e1-e8. doi:10.2105/AJPH.2019.305543).