Opioid rotation (OR) is used to decrease patients' cancer-related pain and mitigate opioid-induced adverse effects. There is limited evidence regarding its effect on symptoms and morphine equivalent daily dose (MEDD). The objective of this study was to investigate the effects of OR on pain scores, Edmonton Symptom Assessment Score (ESAS), and MEDD in patients with cancer. Retrospective observational study in an outpatient supportive care clinic using a within-subject design to analyze data collected over 34 months. Study included 676 patients with 217 rotations identified in 128 patients at supportive care clinic at a National Cancer Institute (NCI) Cancer Center. OR were identified and analysis compared the pre-visit data with the subsequent post-visit data following OR using paired t-tests. Primary endpoints included pain scores, total ESAS, and MEDD for OR and these endpoints were compared amongst rotations to specific opioid analgesics. Following OR, there was a statistically significant reduction in mean pain scores from 6.25 at the pre-visit to 5.75 following OR. Of the 194 ORs, 29.90% were successful in reducing patients' pain by either 30% or by 2-points. Only rotations to morphine, oxycodone, and methadone correlated with significant decreases in pain scores. Overall, OR did not correlate with significant changes in ESAS or MEDD. Only rotations to methadone correlated with a significant reduction in MEDD. These findings suggest OR is associated with decreased pain scores without increasing MEDD. Of the agents compared, only rotations to methadone correlated with both a significant reduction in pain scores and in MEDD.