Objective: To observe treatment effects and safety of fluvoxamine combined with oxycodone prolonged-release tablets in treating patients with moderate to severe cancer pain. Methods: 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. Results: 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 $4.9{\pm}0.8$ and $5.1{\pm}0.8$, respectively; and decreased to $1.8{\pm}1.1$ and $1.2{\pm}1.1$ after treatment, respectively. Pain intensity was significantly reduced in the treatment group (P=0.028). Average daily consumption of oxycodone prolonged-release tablets was ($54.0{\pm}19.6$) mg and ($44.7{\pm}18.7$) 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 $8.3{\pm}1.1$ and $8.3{\pm}1.1$, respectively; and pain intensity after treatment decreased to $2.9{\pm}1.0$ and $2.3{\pm}1.0$. Pain intensity was significantly reduced in the treatment group, with statistical significance (P=0.026). Average daily consumption of oxycodone prolonged-release tablets was ($132.0{\pm}42.2$) mg and ($110.7{\pm}33.9$) 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). Conclusion: 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.