ABSTRACT: Objective:Despite the long-term decline, heart disease has remained the leading cause of death in the United States (US) over the past eight decades, accounting for 23% of all deaths in 2017. Although psychological distress has been associated with cardiovascular disease mortality, the relationship between different psychological distress levels and heart disease mortality in the US has not been analyzed in detail. Using a national longitudinal dataset, we examined the association between levels of psychological distress and US heart disease mortality. Methods:We analyzed the Kessler 6-item psychological distress scale as a risk factor for heart disease mortality using the pooled 1997-2014 data from the National Health Interview Survey (NHIS) linked to National Death Index (NDI) (N=513,081). Cox proportional hazards regression was used to model survival time as a function of psychological distress and sociodemographic and behavioral covariates. Results:In Cox models with 18 years of mortality follow-up, the heart disease mortality risk was 121% higher (hazard ratio [HR]=2.21; 95% CI=1.99,2.45) in adults with serious psychological distress (SPD) (p<0.001), controlling for age, and 96% higher (HR=1.96; 95% CI=1.77,2.18) in adults with SPD (p<0.001), controlling for age, gender, race/ethnicity, immigrant status, education, marital status, poverty status, housing tenure, and geographic region when compared with adults without psychological distress. The relative risk of heart disease mortality associated with SPD decreased but remained significant (HR=1.14, 95% CI=1.02,1.28) after controlling for additional covariates of smoking, alcohol consumption, self-assessed health, activity limitation, and body mass index. There was a dose-response relationship, with relative risks of heart disease mortality increasing consistently at higher levels of psychological distress. Moreover, the association varied significantly by gender and race/ethnicity. The relative risk of heart disease mortality for those who experienced SPD was 2.42 for non-Hispanic Whites and 1.76 for non-Hispanic Blacks, compared with their counterparts who did not experience psychological distress. Conclusions and Global Health Implications:US adults with serious psychological distress had statistically significantly higher heart disease mortality risks than those without psychological distress. These findings underscore the significance of addressing psychological well-being in the population as a strategy for reducing heart disease mortality.