Background: Our objective was to examine differences in health-related quality of life (HRQOL) between people with coronary heart disease (CHD) and those without this condition in a population-based sample of U.S. adults and to examine the interaction between CHD and diabetes on HRQOL. Methods and Results: We performed a cross-sectional analysis of data from 50,573 participants aged ≥18 years from 10 states of the 2004 Behavioral Risk Factor Surveillance System (BRFSS). Data were self-reported. HRQOL was assessed with the Centers for Disease Control and Prevention (CDC) HRQOL-4 measures. After adjusting for age, gender, race or ethnicity, educational status, marital status, employment status, smoking status, body mass index (BMI), and alcohol use, the percentages of women without CHD who, during the previous 30 days, reported experiencing ≥14 physically unhealthy days, ≥14 mentally unhealthy days, and ≥14 activity-limitation days were 7.5%, 10.4%, and 3.6%, respectively, compared with 16.5% (odds ratio [OR] = 2.49, 95% confidence interval [CI] 2.02, 3.07), 14.5% (OR = 1.58, 95%, CI 1.22, 2.04), and 8.4% (OR = 2.56, 95% CI 1.98, 3.30) for women with CHD. The adjusted percentages of men without CHD who reported experiencing ≥14 physically unhealthy days, ≥14 mentally unhealthy days, and ≥14 activity-limitation days were 5.6%, 6.0%, and 3.0%, respectively, compared with 10.1% (OR = 1.85, 95% CI 1.47, 2.32), 8.7% (OR = 1.32, 95% CI 1.00, 1.74), and 6.4% (OR = 1.99, 95% CI 1.49, 2.66) for men with CHD. A higher adjusted percentage of women with CHD reported experiencing ≥14 physically unhealthy days (p < 0.001) and ≥14 mentally unhealthy days (p = 0.002) but not ≥14 activity-limitation days (p = 0.090) than men with CHD. Conclusions: People with CHD have significantly impaired HRQOL compared with those without CHD. HRQOL among women with CHD is worse than that among men with CHD.