We present a case in which serotonin syndrome developed immediately after the initiation of low-dose methadone following an increase in oxycodone dose and the initiation of duloxetine. The symptoms of serotonin syndrome were alleviated and later disappeared upon cessation of methadone alone. The case was a 47-year-old woman with a desmoid tumor. The administration of duloxetine (20 mg/day) was initiated while the patient took oxycodone sustained-release tablets (40 mg/day). The following day, excessive perspiration, chills, and tremors appeared after the initiation of 15 mg/day methadone. Discontinuation of methadone led to an alleviation of the symptoms which completely disappeared 3 days later. The results suggest that low-dose methadone can trigger serotonin syndrome as early as after the first dose. Thus, it is important to be aware of the risks and to immediately take action if symptoms appear.