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Methadone can be an effective drug for cancer pain but it can also be difficult to use safely. It has been recommended that rotation to methadone from other opioids be undertaken in a hospital setting. The purpose of the study was to characterize the safety, toxicities, and outcomes of outpatient rotation to methadone for severe cancer pain in a heavily pretreated cohort of cancer patients. Data were collected through a retrospective review of consecutive patients from a tertiary level cancer pain clinic. Twenty-nine patients were rotated to methadone, 13 (45%) due to opioid toxicity and 16 (55%) because of either cost or difficulty swallowing their prior opioid. Eleven of 29 patients (38%) failed methadone due to rapidly progressive cancer, dose-limiting side effects, or other reasons, but the other patients were successfully rotated to methadone. Pain usually improved following rotation to methadone, but drowsiness from methadone was common. On average, it took 32 days to successfully rotate to methadone in the outpatient setting. Cancer patients with advanced disease and severe pain can be safely and effectively rotated to methadone in the outpatient setting. It takes considerably longer to stabilize these patients than patients on lower doses of opioid or those titrated in the inpatient setting. A careful monitoring system is needed to screen for evidence of toxicity.