© 2015 American Heart Association, Inc. Background-Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results-Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women's Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P=0.46. However, CaD supplementation had differential effects (P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.460.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P=0.51, in the high-risk subgroups. Conclusions-CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism.