In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up. In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF 45 (mean age 64 years, 26 women, 17 non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class IIIIV symptoms (n 2223), LVEF 25 (n 2256), and cardiothoracic ratio (CTR) 55 (n 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA IIIIV [hazard ratio (HR) 0.65; 95 confidence interval (CI) 0.570.75; P 0.001], LVEF 25 (HR 0.61; 95 CI 0.530.71; P 0.001), and CTR 55 (HR 0.65; 95 CI 0.570.75; P 0.001). Digoxin-associated HRs (95 CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA IIIIV, LVEF 25, and CTR 55 were 0.88 (0.800.97; P 0.012), 0.84 (0.760.93; P 0.001), and 0.85 (0.770.94; P 0.002), respectively. Digoxin improves outcomes in chronic HF patients with NYHA class IIIIV, LVEF 25, or CTR 55, and should be considered in these patients.