Background: Frailty may modify the risk benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. Objective: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). Design: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124) Setting: 410 sites in 20 countries. Patients: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. Intervention: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Measurements: The primary outcome was worsening HF or cardiovascular death. Results: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI ≤0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI ≥0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were 3.5 (95% CI, 5.7 to 1.2), 3.6 (CI, 6.6 to 0.5), and 7.9 (CI, 13.9 to 1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. Limitation: Enrollment criteria precluded the inclusion of very high-risk patients. Conclusion: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients.