OBJECTIVE：To compare th e clinical efficacy and safety of trazodone combined with venlafaxine and venlafaxine in the treatment of major depressive disorder （MDD）. METHODS ：Totally 160 patients with MDD who were treated in our hospital from Sept. 2018 to Oct. 2020 were all enrolled and divided into control group （80 cases）and observation group （80 cases）according to random number table. Control group was treated with V enlafaxine hydrochloride sustained-release tablets 75 mg orally，once every morning. Observation group was additionally treated with Trazodone hydrochloride tablets 25 mg orally ，twice a day，on the basis of control group. The dosage was adjusted according to the efficacy and tolerance. Hamilton depression scale 24 （HAMD-24），Montgomery-Asperger depression scale （MADRS） and Pittsburgh sleep quality index （PSQI） were compared between 2 groups before and after treatment. Clinical efficacies were compared and the occurrence of ADR were recorded. RESULTS：A total of 12 patients were expelled ，and 148 patients were eventually included ，involving 73 cases in control group and 75 cases in observation group. Before treatment ，there was no significant differences in HAMD- 24，MADRS or PSQI scores between 2 group（P＞0.05）. After 1，3，5 and 8 weeks of treatment ，HAMD-24 and MADRS scores of 2 groups were significantly lower than before treatment ，and the observation group was significantly lower than the control group （P＜0.05）. PSQI scores of observation group were significantly lower than before treatment and control group during the same period （P＜0.05），while there was no significant difference in PSQI scores of control group before and after treatment （P＞0.05）. The total response rate of observation group （96.00％）was significantly higher than control group （86.30％）（P＜0.05）. There was no statistical significance in the incidence of ADR between 2 groups（P＞0.05）. CONCLUSIONS ：Trazodone combined with venlafaxine and venlafaxine alone both have good efficacy and similar safety in the treatment of MDD ， but clinical efficacy of trazodone combined with venlafaxine is better.