BACKGROUND Cardiac resynchronization therapy (CRT) typically is attempted with biventricular pacing (BiVP). One-third of patients are nonresponders. His-bundle pacing (HBP) has been evaluated as an alternative means of effecting CRT because it generates truly physiologic ventricular activation, as evidenced in part by the morphologic identity between normally conducted and paced QRS complexes. OBJECTIVE The purpose of this study was to assess the feasibility of, and clinical response to, permanent HBP as an alternative to BiVP in CRT-indicated patients. METHODS Patients were implanted with a right atrial pacing lead, defibrillation lead, left ventricular (LV) lead via the coronary sinus, and HBP lead. His and LV leads were plugged into the LV port via a Y-adapter. After successful implant, patients were randomized in single patient-blinded fashion to either HBP or BiVP. After 6 months, patients were crossed over to the other pacing modality and followed for another 6 months. Quality-of-life assessments, echocardiographic measurements, New York Heart Association classification, and 6-minute hall walk test were obtained at baseline and at each 6-month follow-up. RESULTS Twenty-nine patients were enrolled; 21 (72%) demonstrated electrical resynchronization (QRS narrowing) at implant. Twelve patients completed the crossover analysis at 1 year. Clinical outcomes (quality of life, New York Heart Association functional class, 6-minute hall walk test, LV ejection fraction) were significantly improved for both pacing modes compared with baseline measures. CONCLUSIONS In this crossover comparison between HBP and BiVP, HBP was found to effect an equivalent CRT response. QRS narrowing was observed in 21 of 29 patients, suggesting this approach may be feasible in more patients with left bundle branch block than previously assumed.