The study evaluated the clinical safety, performance, and efficacy of sequential biventricular pacing in the InSync III (Model 8042) biventricular stimulator in a multicenter, prospective 3-month study and assessed the proper functioning of features aiming at improving biventricular AV therapy delivery. The system was successfully implanted in 189 (95.9%) of 198 patients with symptomatic systolic heart failure and a prolonged QRS complex duration. Patients significantly improved their 6-minute hall walk distance (baseline 339 +/- 92 vs 3-month 422 +/- 127 meter, P < 0.001) and NYHA class (baseline 3.1 +/- 0.5 vs 3-month 1.9 +/- 0.7, P < 0.001). Echocardiographic optimization of sequential biventricular pacing showed an improvement in stroke volume compared to simultaneous stimulation (sequential 68 +/- 24 mL vs simultaneous 56 +/- 23 mL, P < 0.001) at baseline and at 3 months. In 88% (30/34) of the patients these improvements were seen within a small range of V-V delays of +/-20 ms and in 94% (32/34) within V-V delays of +/-40 ms. In contrast, programming beyond this range reduced stroke volume below that during simultaneous biventricular pacing. The device functioned as expected. LV lead dislodgement was observed in 12 patients and phrenic nerve stimulation required lead repositioning in 2 patients. Eight patients died during the study. Patient survival at 3 and 6 months was 97 +/- 2% and 94 +/- 2%, respectively. Cause of death was cardiac (n = 7), heart failure related (n = 3), arrhythmia related (n = 2), and unknown (n = 2). In conclusion, this sequential biventricular pacemaker was safe and efficacious.