Background: Studies have shown that oral oxycodone sustained-release (SR) tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycodone SR tablets for opioid titration of cancer pain. Methods:Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5 [95%CI: 2.5-11.5] hours vs. 16.0 [95%CI: 11.5-22.5] hours; p< 0.001). PCSA reduced the frequency of breakthrough pain (Btp), especially in patients with opioid tolerance. The number of Btp was 121±28 times and 186±31 times in the PCSA and oxycontin groups, respectively (p< 0.001). The 12-hour numeric rating scale (NRS) score was significantly lower in the PCSA group than that in the oxycontin group (median [95%CI], 2.5 [95%CI: 1.4-2.9] vs. 4.4[95%CI: 3.2-5.8]) (p< 0.001). Similar equivalent morphine consumption and significantly improved quality of life were observed in the two groups. No between-group difference in the incidence of opioid-related adverse effects was observed. Conclusions: Compared with oral oxycodone SR tablet, the use of PCSA with hydromorphone achieved faster pain relief and a shorter titration duration for patients with cancer pain without increasing adverse events. Clinical trial information: ChiCTR2000037845.