Background: The aim of this study was to evaluate the effect of high intensity, interval exercise on quality of life (QoL) and depression status, in chronic heart failure (CHF) patients. Methods: A randomized controlled trial (phase III). Of the 100 consecutive CHF patients (NYHA classes II-IV, ejection fraction≤50%) that were randomly allocated to exercise intervention (n = 50, highintensity intermittent endurance training 30 s at 100% of max workload, 30 s at rest, for 45 min/day-by-12 weeks) or no exercise advice (n = 50), 72 (exercise group, n = 33, 63±9 years, 88% men, 70% ischemic CHF and control group, n = 39, 56±11 years, 82% men, 70% ischemic CHF) completed the study. QoL was assessed using the validated and translated Minnesota Living with Heart Failure questionnaire. Depressive symptomatology was evaluated using the validated and translated Zung Depression Rating Scale (ZDRS). Maximal oxygen uptake (V O2max) and carbon dioxide production (V CO2max) were also measured breath-bybreath. Results: Data analysis demonstrated that in the intervention group MLHFQ score was reduced by 66% (P = 0.003); 6-min-walk distance increased by 13% (P < 0.05), V O2max level increased by 31% (P = 0.001), V CO2max level increased by 28% (P = 0.001) and peak power output increased by 25% (P = 0.001), as compared with the control group. Conclusion: High intensity, systematic aerobic training, could be strongly encouraged in CHF patients, since it improves QoL, by favorably modifying their fitness level.