BACKGROUND We studied the effects on cardiac function of pacing two right and two left ventricular sites in normal and failing hearts with a normal QRS duration. RESULTS Hemodynamic parameters were studied in isoflurane-anesthetized dogs with normal hearts and dogs with heart failure induced by rapid ventricular pacing. Unipolar intramyocardial electrodes were placed at the high right atrium and the apex (A) and base (B) of the left (L) and right (R) ventricles (V). Data were collected after pacing for 5 to 20 minutes. In normal dogs, without bundle branch block (BBB), pacing at either the apex or the base of the left ventricle increased cardiac output by approximately 10% compared with right ventricular apex (RVA) pacing with an AV delay of 0 msec. Positive dP/dt increased approximately 10% during four-site left and right ventricular apex and base (LRVAB) pacing compared with RVA pacing. In dogs with heart failure but without BBB, cardiac output increased by 8.5% (P < 0.01) during four-site ventricular pacing with AV delays of 0 and 60 msec compared with RVA pacing. Positive dp/dt increased by 23.5% (P < 0.001) with an AV delay of 0 msec and 9.6% (P < 0.001) with an AV delay of 60 msec during LRVAB pacing compared with RVA pacing. His-bundle pacing was associated with increased cardiac output compared with RVA pacing. CONCLUSIONS We conclude that pacing simultaneously at two right and two left ventricular sites significantly improves cardiac function compared with single RVA pacing, with or without sequential AV synchrony, in dogs with rapid ventricular pacing-induced heart failure and no BBB.