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We studied the association of coronary artery calcium (CAC) and risk of heart failure with preserved ejection fraction (HFpEF) among men and women in a multiethnic cohort. Coronary artery disease is a risk factor for development of HFpEF and assessment of subclinical atherosclerosis using CAC may allow for the early identification of patients at risk for HFpEF. We used data from the Multi-Ethnic Study of Atherosclerosis. CAC was measured at baseline in all participants. Incident HFpEF was defined as heart failure hospitalization with left ventricular ejection fraction ≥50%. Multivariable-adjusted Cox proportional hazards models were used to calculate HFpEF risk by CAC categories (0, 1 to 100, 101 to 300, and >300) and by CAC (continuous), stratified by gender and race/ethnicity. Of 6809 total participants, 127 incident HFpEF cases (1.8%) were ascertained. Mean age was 62 years (±10 years), and the participants were 53% female, 38% White, and 12% Black. In adjusted analysis, CAC >300 was associated with increased risk of HFpEF (hazard ratio [HR] 1.68, 95% confidence interval [95 CI] 1.00, 1.83); however, this was significant only in women (HR 2.82, 95% CI 1.32, 6.00 vs HR 0.91, 95% CI 0.46, 1.82 for men, interaction p = 0.03). Similarly, CAC modeled as a continuous variable was strongly predictive in women but not in men. In conclusion, measurement of CAC, a marker of coronary atherosclerosis, may stratify risk of HFpEF beyond traditional risk factors for women. Further investigation is needed to better understand potential gender differences in pathophysiology and presentation of HFpEF., (Copyright © 2017 Elsevier Inc. All rights reserved.)