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Benefit from cardiac resynchronization therapy (CRT) is likely influenced by the location of the left ventricular (LV) lead.To evaluate the association of LV lead position with outcome after CRT.Two-hundred and fifty patients with LV dysfunction, New York Heart Association (NYHA) class III (68%) or IV (32%) symptoms, and QRS durations ≥120 ms were followed for a median of 30 months post-CRT. LV lead position was categorized as anterior (n = 20, 8%), lateral (n = 128, 51%), or posterior (n = 102; 41%) using postero-anterior and lateral postoperative chest radiographs.Median age was 69 years and most (68%) had ischemic LV dysfunction. Clinical response, defined by a ≥1 NYHA class reduction, was lower in patients with an anterior (30%) versus lateral (76%) or posterior (73%) lead position (p = 0.001). An anterior versus nonanterior position was independently associated with a two to three-fold higher risk for nonresponse to CRT, cardiovascular death, death from worsening heart failure or cardiac transplantation, and death from any cause. Repositioning of the LV lead from an anterior to a nonanterior position in seven patients who had not clinically responded to CRT after ≥6 months resulted in clinical improvement in all cases.An anterior versus nonanterior LV lead position is independently associated with an increased likelihood of nonresponse to CRT and a higher risk of serious outcomes. Repositioning of an anteriorly placed LV lead to a nonanterior position should be considered in CRT nonresponders.