The SEM, XRD characterization and copper content phase analysis were conducted on the refractory copper oxide at a certain place of Yunnan Province to ensure the mineral processing technology of sulfuration flotation. Besides, the single factor experiment was carried out and the flotation parameters were optimized through response surface methodology. The results showed that both of the grade of copper concentrate and the p value of recovery model were less than 0.05. The grinding fitness and the dosage of phosphoric acid ethylenediamine had a significant effect on the recovery of copper concentrate, and the dosage of phosphoric acid ethylenediamine had a significant effect on the grade of copper concentrate. The optimum flotation conditions of response surface methodology were the grinding fitness less than 0.074 mm accounting for 86.07%, the dosage of sodium sulphide 2012.75 g/t, the dosage of phosphoric acid ethylenediamine 132.19 g/t. Under these conditions, the copper concentrate recovery rate of 79.007% and grade of 22.156% were obtained. Basically, the results of flotation experiment and response surface methodology optimization were the same. In the closed-circuit flotation flowsheet under the optimized flotation conditions, the obtained copper concentrate contained 21.93% copper and the recovery rate was 76.23%.