Abstract: Objective To explore the clinical effect of venlafaxine combined with quetiapine in the treatment of patients with severe depression in the acute phase. Methods A total of 100 patients with severe depression were randomly divided into observation group and control group. The observation group was treated with venlafaxine and quetiapine, while the control group was treated with venlafaxine and placebo. After 4 and 8 weeks of treatment, the scores of Hamilton Depression Scale(HAMD)and Hamilton Anxiety Scale(HAMA)were compared between two groups, and the safety of the drugs was assessed by Treatment Emergent Symptom Scale(TESS). Results There were no significant differences in HAMD and HAMA scores between the two groups before treatment(P>0.05). After 4 and 8 weeks of treatment, the scores of HAMD and HAMA in both groups were significantly lower than those before treatment(P<0.05), and the scores of HAMD and HAMA in the observation group were significantly lower than those in the control group(P<0.05). After 4 weeks of treatment, the effect of the observation group was significantly better than that of the control group(P<0.05). After 8 weeks of treatment, the effect of the observation group was better than that of the control group, but no significant difference was found(P>0.05). After 4 and 8 weeks of treatment, there was no significant difference in TESS score between the two groups(P>0.05), TESS score were lower at the 8^th week when compared with the data at the 4^th week(P<0.05). After 4 and 8 weeks of treatment, the number of patients with insomnia and hypertension in the observation group - was significantly less than that in the control group(P<0.05). Conclusion Venlafaxine combined with quetiapine is effective and safe in the treatment of patients with acute severe depression in acute phase, which can reduce scores of HAMD and HAMA, and incidence rate of insomnia and hypertension.