In the Digitalis Investigation Group trial, digoxin-associated decrease in the combined end point of heart failure (HF) hospitalization or HF mortality was significant in systolic but not in diastolic HF. To assess whether this apparent disparity could be explained by differences in baseline characteristics and sample size, we used propensity score matching to assemble a cohort of 916 pairs of patients with systolic and diastolic HF who were balanced in all measured baseline covariates. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of the effect of digoxin on outcomes separately in systolic and diastolic HF, at 2 years (protocol prespecified), and at the end of 3.2 years of median follow-up. HF hospitalization or HF mortality occurred in 28% and 32% of patients with systolic HF (HR digoxin vs placebo 0.85, 95% CI 0.67 to 1.08, p = 0.188) and 20% and 25% in those with diastolic HF (HR 0.79, 95% CI 0.60 to 1.03, p = 0.085) receiving digoxin and placebo, respectively. At 2 years, HRs for this combined end point were similar for systolic HF (0.72, 95% CI 0.55 to 0.95, p = 0.022) and diastolic HF (0.69, 95% CI 0.50 to 0.95, p = 0.025). Digoxin also decreased 2-year HF hospitalization in systolic HF (HR 0.73, 95% CI 0.54 to 0.97, p = 0.033) and diastolic HF (HR 0.64, 95% CI 0.45 to 0.90, p = 0.010). In conclusion, as in patients with systolic HF, digoxin was equally effective in those with diastolic HF, who constitute half of all patients with HF, yet have few evidence-based therapeutic options.