Morphine, oxycodone, and fentanyl are commonly used to control cancer pain. Because these drugs have differences in receptor affinity or pharmacokinetic parameters, changing the opioid formulation may result in an unexpected outcome, depending on the patient’s condition. This study investigated whether low serum protein levels influence the effectiveness of opioid rotation by determining the impact of serum albumin levels on the analgesic effect before and after opioid rotation from morphine or oxycodone to fentanyl in cancer patients. The patients were classified into 3 groups according to their serum albumin levels before opioid rotation: group 1, <2.5 g/dL; group 2, from 2.5 g/dL to <3.0 g/dL; and group 3, ≥3.0 g/dL. There was no significant change in the percentage of patients with good pain control after rotation in group 1 or group 2; however, the percentage of patients with good pain control increased significantly in group 3. When the percentage of patients whose numerical rating scale scores increased, were unchanged, or decreased after rotation were compared, a significant difference in the percentage of those showing improvement was noted among the 3 groups and between groups 1 and 3. These findings suggest that monitoring serum albumin levels during fentanyl therapy is useful for pain management, and that the effectiveness of opioid rotation to fentanyl in patients with serum albumin levels of <2.5 g/dL should be carefully evaluated after rotation.