Objective To investigate the effect and safety of venlafaxine augmented with amisulpride in the treatment of major depressive disorder. Methods Fifty patients with major depressive disorder were randomly divided into control group treated with venlafaxine (n=25) and study group treated by venlafaxine augmented with amisulpride (n=25). The treatment lasted 8 weeks. Hamilton Depression Rating Scale (HAMD) and Treatment Emergent Symptom Scale (TESS) were used to evaluate the effect and safety of therapy before and 1, 2, 4, and 8-week after treatment. The serum level of IL-18 was detected at each time points in two groups. Results After treatment for 2, 4 and 8 weeks, the serum levels of IL-18 were significantly decreased in study group than that of control group (P<0.05). The serum levels of IL-18 were gradually reduced with the extended treatment time in two groups. There was no interaction between two groups and different processing times. Scores of HAMD decreased gradually after treatment in two groups. Scores of HAMD were significantly lower after treatment than that before treatment in study group (P<0.05). Scores of HAMD were significantly lower after treatment than that before treatment except for one-week treatment in control group (P<0.05). There were no significant differences in HAMD scores before treatment and one-week treatment of two groups. Scores of HAMD were significantly lower 2,4 and 8 weeks after treatment in study group compared with those of control group (P<0.05). There was a interaction between groups and processing times (P<0.05). The effective rates increased in study group (96%) than control group (76.0%). The adverse effects were less in two groups. Conclusion The low dose of amisulpride helps to improve the efficacy of venlafaxine in the treatment of major depressive disorder, which has good security and can inhibit inflammatory reaction.