Controlled-release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer-pain patients randomized to double-blind treatment with controlled-release oxycodone (n = 48) or controlled-release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled-release oxycodone and 81% of controlled-release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0=none to 3=severe) decreased from baseline within each group (p≤ 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled-release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled-release morphine (no significant between-group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled-release morphine (n = 2). Visual analog scores (VAS) for ‘itchy’ and ’scratchin’ were lower with controlled-release oxycodone (p≤ 0.044), as was peak-to-trough fluctuation in steady-state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine-6-glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.0001). Controlled-release oxycodone was as effective as controlled-release morphine in relieving chronic cancer-related pain, and as easily titrated to the individual's need for pain control. While adverse experiences were similar, controlled-release oxycodone was associated with less itching and no hallucinations. Controlled-release oxycodone provides a rational alternative to controlled-release morphine for the management of moderate to severe cancer-related pain.