Background Prior studies suggested lower risk of heart failure (HF) in individuals taking H₂ receptor antagonists (H2RA) compared with H2RA nonusers in relatively small studies. We evaluated the association of H2RA use and incident HF in postmenopausal women in the large-scale WHI (Women's Health Initiative) study. Methods and Results This study included postmenopausal women from the WHI without a history of HF at baseline. HF was defined as first incident hospitalization for HF and physician adjudicated. Multivariable Cox proportional hazards regression models evaluated the association of H2RA use as a time-varying exposure with HF risk, after adjustment for demographic, lifestyle, and medical history variables. Sensitivity analyses examined (1) risk of HF stratified by the ARIC (Atherosclerosis Risk in Communities) score, (2) propensity score matching on H2RA use, (3) use of proton pump inhibitors rather than H2RA nonuse as the referent, and (4) exclusion of those taking diuretics at baseline. The primary analysis included 158 854 women after exclusion criteria, of whom 9757 (6.1%) were H2RA users. During median 8.2 years of follow-up, 376 H2RA users (4.9 events/1000 person-years) and 3206 nonusers (2.7 events/1000 person-years) developed incident HF. After multivariable adjustment, there was no association between H2RA use and HF in the primary analysis (hazard ratio, 1.07; 95% CI, 0.94-1.22; P=0.31) or in any of the sensitivity analyses. Conclusions Clinical H2RA use was not associated with incident HF among postmenopausal women. Future studies are needed to evaluate potential effect modification by sex, HF severity, or patterns of use on H2RA exposure and HF risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00000611.