Abstract Context Oxycodone and morphine are recommended as first-choice opioids for moderate/severe cancer pain, but evidence about their relative tolerability has significant methodological limitations. Objectives This study was mainly aimed at comparing the risk of developing adverse events (AEs) with controlled-release oral morphine vs. oxycodone; secondary aims were comparing their analgesic efficacy and testing heterogeneity in tolerability across different age and renal function subgroups. Methods An open-label multicenter RCT (EudraCT number: 2006-003151-21) was carried out in patients with moderate/severe cancer pain. At baseline, 7 and 14 days, patients scored on 0–10 rating scales (0–10 numerical rating scale) the intensity of pain and of a list of common opioid side effects. The primary end point was the percentage of patients reporting an AE (a worsening ≥ 2 points on any of the listed side effects); tolerability by subgroups and average follow-up pain intensity were compared through regression models. Results One hundred eighty-seven patients were enrolled (47% of originally planned). Intention to treat (ITT) analysis ( N  = 185, morphine 94, oxycodone 91) did not show any difference in the risk of developing AEs (risk difference −0.6%, 95% CI −11.0% to 9.9%) nor in analgesia (0–10 numerical rating scale pain intensity difference −0.28, 95% CI −0.83 to 0.27). No evidence of heterogeneity of tolerability across age and renal function patient subgroups emerged. Conclusion This trial failed to show any difference in tolerability and analgesic efficacy of morphine and oxycodone as first-line treatment for moderate/severe cancer pain but results interpretation is difficult due to lack of power, potential bias from open-label design, and concerns about assay sensitivity. These data, however, can significantly contribute to future meta-analyses comparing WHO Step-III opioids and are relevant in designing future randomized studies.