Oxycodone is a widely used opioid for cancer analgesia. A 62-year-old woman who was diagnosed with metastatic malignant melanoma (stage Ⅳ) received oxycodone for pain control. While adequate analgesia was achieved at 60 mg/day of oxycodone without central adverse reactions, she eventually developed laxative-resistant constipation. Bowel movements were induced by an oral administration of a prokinetic agent, erythromycin (800 mg/day), whereas the patient developed somnolence four days after the commencement of the drug. Her symptoms disappeared promptly after withdrawal of erythromycin (dechallenge), and administration of oxycodone was continued. The dose of oxycodone was increased to 120 mg/day without central adverse reactions. Two weeks later she was given erythromycin (re-challenge) for refractory constipation and again developed nausea. Upon withdrawal of erythromycin (de-challenge), the symptom disappeared within two days while the same dose of oxycodone (120 mg/day) was maintained. There was a definite causal relationship between co-administration of the two drugs and developments of central adverse reactions, since the Naranjo's probability score of the drug interaction was 9. We considered that the developments of somnolence and nausea may be attributed to the drug interaction between oxycodone and erythromycin. An assumed mechanism might have been an inhibition of cytochrome P-450 (CYP) 3A4 by erythromycin and a resultant increase in plasma concentrations of oxycodone. Analyses of the Japanese Adverse Drug Event Report (JADER) and the FDA Adverse Event Reporting System (FAERS) databases revealed no significant excessive signals of somnolence or nausea for patients receiving oxycodone with macrolide antibiotics. We consider that a caution should be exercised for prescribing erythromycin to patients receiving oxycodone. Spontaneous reporting systems may not be sensitive for detecting a drug interaction mimicking commonly observed augmented pharmacologic effects of a victim drug.