Rationale: Despite differences in chronic obstructive pulmonary disease (COPD) comorbidities, race- and sex-based differences in all-cause mortality and cause-specific mortality are not well described. Objectives: To examine mortality differences in COPD by race-sex and underlying mechanisms. Methods: Medicare claims were used to identify COPD among REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort participants. Mortality rates were calculated using adjudicated causes of death. Hazard ratios (HRs) for mortality comparing race-sex groups were modeled with Cox proportional hazards regression. Results: In the 2,148-member COPD subcohort, 49% were women, and 34% were Black individuals; 1,326 deaths occurred over a median 7.5 years (interquartile range, 3.9-10.5 yr) follow-up. All-cause mortality per 1,000 person-years comparing Black versus White men was 101.1 (95% confidence interval [CI], 88.3-115.8) versus 93.9 (95% CI, 86.3-102.3; P = 0.99); comparing Black versus White women, all-cause mortality per 1,000 person-years was 74.2 (95% CI, 65.0-84.8) versus 70.6 (95% CI, 63.5-78.5; P = 0.99). Cardiovascular disease (CVD) was the leading cause-specific mortality among all race-sex groups. HR for CVD and chronic lung disease mortality were nonsignificant comparing Black versus White men. HR for CVD death was higher in Black compared with White women (HR, 1.44; 95% CI, 1.06-1.95), whereas chronic lung disease death was lower (HR, 0.44; 95% CI, 0.25-0.77). These differences were attributable to higher CVD risk factor burden among Black women. Conclusions: In the REGARDS COPD cohort, there were no race-sex differences in all-cause mortality. CVD was the most common cause of death for all race-sex groups with COPD. Black women with COPD had a higher risk of CVD-related mortality than White women. CVD comorbidity management, especially among Black individuals, may improve mortality outcomes.