OBJECTIVE: Methadone may cause detrimental side effects such as corrected QT (QTc) prolongation. However, methadone may be desirable in patients with advanced cancer and those with heart disease who have intractable pain. Therefore, we aimed to evaluate the safety and efficacy of initiating methadone for cancer pain in patients at high risk of methadone-induced QTc prolongation. DESIGN: A retrospective cohort study. SETTING: Single center. PATIENTS: Sixty-four patients with cancer who started oral methadone to relieve pain and underwent 12-lead electrocardiogram monitoring at baseline and 1-2 weeks after initiation of methadone therapy from January 1, 2013, to March 31, 2022, were enrolled. MAIN OUTCOME MEASURES: The primary endpoints were the change in QTc from baseline after oral methadone therapy and the difference in methadone doses between the high- and low-risk groups for methadone-induced QTc prolongation. RESULTS: None of the patients developed clinically significant methadone-induced QTc prolongation or any adverse events attributable to cardiotoxicity, although 32 patients (50.0 percent) had heart disease or prolonged QTc before oral methadone initiation. Moreover, the high-risk group received a lower dose of opioid analgesics prior to methadone administration. For this reason, they started with a lower methadone dose than the low-risk group. CONCLUSIONS: Even in patients with heart disease or prolonged QTc at baseline, methadone may be safely administered by initiating low-dose methadone when the dose of other opioids is low and by adjusting the concomitant medications that can interact with methadone.