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To analyze the efficacy of a novel palivizumab protocol for hemodynamically significant congenital heart disease (hsCHD) in subtropical areas without clear respiratory syncytial virus seasonality.Since July 2013, the National Health Insurance program has provided reimbursement for palivizumab prophylaxis with a novel monthly protocol in selected patients with hsCHD under 1 year of age. We performed a multicenter study to assess the trend of respiratory syncytial virus hospitalizations in patients with hsCHD from 2010 to 2016 during the prepalivizumab, transition, and postpalivizumab periods, and compared treatment and propensity-matched control groups.A total of 747 patients were enrolled in the study group and 809 in the control group. The male:female was 836:720. Cyanotic CHD was observed in 42.9% of patients. The mean age at diagnosis of CHD was 32.9 days. After 516 685 patient-days of follow-up and a mean of 3.9 doses of palivizumab in the treatment group, respiratory syncytial virus hospitalization rates decreased by 53% and 49% before and after match compared with the control group (P = .009 and .029, respectively). Hospitalization days and intensive care unit admission rate also decreased similarly in the treatment group. The efficacy of this protocol was more prominent in patients with cyanotic hsCHD. The annual respiratory syncytial virus-associated hospitalization rates also decreased significantly from the prepalivizumab to the palivizumab period (from 4.8% to 2.0%; P = .038).Palivizumab prophylaxis through the novel monthly protocol for patients with hsCHD is effective in reducing respiratory syncytial virus-related hospitalizations.