To observe treatment effects and safety of fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain. Patients confirmed pathologically with cancer and complicated with moderate to severe pain, were divided into control and experimental groups. Oxycodone prolonged-release tablets, with or without fluvoxamine, were administrated to all study patients until pain relief. Degree of pain relief, dose of oxycodone prolonged-release tablets, side effects and quality of life were compared before and after treatment. In total, 120 patients were recruited. No statistically significant difference was detected regarding age, gender, types of cancer, KPS between two groups of patients (P> 0.05). Baseline pain score of patients with moderate pain in treatment and control group was 4.9±0.8 and 5.1±0.8, respectively; and decreased to 1.8±1.1 and 1.2±1.1 after treatment, respectively. Pain intensity was significantly reduced in the treatment group (P =0.028). Average daily consumption of oxycodone prolonged- release tablets was (54.0±19.6) mg and (44.7± 18.7) mg respectively, which is lower in treatment grpup than in control group, but the difference was not statistically significant (P=0.065). Baseline pain score of patients with severe pain in treatment and control groups were 8.3±1.1 and 8.3±1.1, respectively; and pain intensity after treatment decreased to 2.9±1.0 and 2.3±1.0. Pain intensity was significantly reduced in the treatment group, with statistical significance (P =0.026). Average daily consumption of oxycodone prolonged-release tablets was (132.0±42.2) mg and (110.7±33.9) mg, respectively, which is lower in treatment group than in control group, and the difference was statistically significant (P=0.035). In terms of quality of life, patients in treatment group had better performance status, daily activity, mood, and sleep than that in control group (P < 0.05). Patients in two groups had similar side effects, eg., constipation, nausea/vomiting, lethargy, dizziness, itchy skin, dysuria, and ataxia. Lower incidence of nausea/vomiting, lethargy, was obtained from patients in treatment than in control group, while significant low constipation was observed in treatment than in control group (35.0% vs 49.2%, P=0.026). Fluvoxamine combined with oxycodone prolonged-release tablets could be more effective in treating patients with cancer pain, and could reduce the dosage of oxycodone prolonged-release tablets and thus be associated with lower side effects, and improved quality of life.