Background: The relationship between psychological stress and heart failure (HF) has not been well studied. We sought to assess the relationship between perceived stress and incident HF. Methods: We used data from the national REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a large prospective biracial cohort study that enrolled community-dwellers aged 45 years and older between 2003 and 2007, with follow-up. We included participants free of suspected prevalent HF who completed the Cohen 4-item Perceived Stress Scale (PSS-4). Our outcome variables were incident HF event, HF with reduced ejection fraction events, and HF with preserved ejection fraction events. We estimated Cox proportional hazard models to determine if PSS-4 quartiles were independently associated with incident HF events, adjusting for sociodemographics, social support, unhealthy behaviors, comorbid conditions, and physiologic parameters. We also tested interactions by baseline statin use, given its anti-inflammatory properties. Results: Among 25,785 participants with a mean age of 64 ± 9.3 years, 55% were female and 40% were Black. Over a median follow-up of 10.1 years, 1109 ± 4.3% experienced an incident HF event. In fully adjusted models, the PSS-4 was not associated with HF or HF with reduced ejection fraction. However, PSS-4 quartiles 2–4 (compared with the lowest quartile) were associated with incident HF with preserved ejection fraction (Q2 hazard ratio 1.37, 95% confidence interval 1.00–1.88; Q3 hazard ratio 1.42, 95% confidence interval 1.03–1.95; Q4 hazard ratio 1.41, 95% confidence interval 1.04–1.92). Notably, this association was attenuated among participants who took a statin at baseline (P for interaction = .07). Conclusions: Elevated perceived stress was associated with incident HF with preserved ejection fraction but not HF with reduced ejection fraction.