The primary objectives of this study were to compare the implantation course of triple-site (double left–single right) and conventional cardiac resynchronization devices. The secondary target was to assess mid-term outcomes of both types of cardiac resynchronization therapy (CRT).Fifty-four patients with NYHA classes III–IV, left ventricular EF≤35% and QRS≥120 ms were included; 27 received triple-site pacemakers (TRIV group), 27 conventional CRT devices (BIV group). Procedural course, clinical data, QRS duration, echocardiographic parameters, peak oxygen consumption (VO2max) and 6-minute walking distance (6MWD) were screened for inter-group differences.Procedure duration was higher in TRIV than in BIV group (197.6 vs. 137.6 min, P<0.001), fluoroscopy exposure and complication-rates were similar. After 3 months of CRT, triple-site pacing was associated with a more significant (P<0.05) NYHA class reduction (by 1.4 vs. 1.0 class, respectively), increase in VO 2 max (2.9 vs. 1.1 mL/kg/min) and 6MWD (98.7 vs. 51.6 m) than conventional CRT. A higher EF and more improved intraventricular synchrony were observed in the TRIV than in the BIV group. The response rate in the TRIV group was 96.3% vs. 62.9% in the conventional group (P=0.002). Triple-site stimulation was an independent predictor of response to CRT (adjusted odds ratio 26.4, P=0.01).Triple-site resynchronization appears to be more beneficial than conventional CRT. Upgrade to triple-site CRT may be considered in non-responders to standard resynchronization.