Phrenic stimulation (PS) may cause intolerable symptoms and prevent CRT delivery in 2-5% of patients. We sought to ensure effective cardiac resynchronization therapy (CRT) delivery by management of PS at the left ventricular (LV) target site. Two hundred and eleven consecutive patients received a CRT device despite PS occurrence at the LV target site at implantation, when a PS-LV difference >2V was achieved by LV stimulation programming (cathode, pacing vector). PS management strategy both at implantation and at follow-up (FU) aimed to keep the target LV implantation site. LV reverse remodeling was assessed by echocardiography before implantation and at follow-up. LV lead placement was lateral/posterolateral in all the 211 patients; 51 of 211 had detectable PS at FU, 26 of 211 (12.3%) were symptomatic. Symptoms occurred more frequently when PS-LV difference was <3V (16/16 vs 10/35, P < 0.001). Cathode and pacing vector reprogramming improved the PS-LV difference and symptoms in 14 of 23 patients. LV output as threshold +0.5V was helpful to manage PS symptoms in patients with a PS-LV ≤2V at FU. Median FU was 34.9 (16-50) months: 12 patients had tolerable PS symptoms, 76% (39/51) were objective responders at echocardiography compared to 74% (119/160) in patients without PS (P = NS). CRT delivery at long term is feasible despite PS at the target LV site. PS management is mandatory in about 12.3% of patients at FU, with 6.6% remaining symptomatic. Symptoms improve at FU when a PS-LV >3V is achieved. Further improvement in lead manufacturing and pacing electronics are awaited to meet this clinical need.