Objective To evaluate the cost effectiveness of four different mechanisms clinical commonly used antidepressants, namely, amitriptyline, escitalopram, mirtazapine and venlafaxine in the treatment of moderate-severe depressive disorder in China and to provide clinicians with some advice. Methods We carried out the cost-effectiveness analysis of four antidepressants by establishing a decision tree model. The parameters uncertainty in the model was estimated through one-way sensitivity analysis. Results In terms of average cost-effectiveness ratio (CER), amitriptyline’s was 45.24 RMB, which was the lowest. And the CERs of mirtazapine, escitalopram and venlafaxine were 273.71 RMB, 332.00 RMB and 716.58 RMB, respectively. While in terms of incremental cost-effectiveness ratio (ICER), venlafaxine was excluded as the dominated strategy. When the threshold value of willingness to pay (WTP) was less than 3 420.92 RMB, amitriptyline was the most cost-effective; when the threshold value ranges between 3 420.92 RMB and 4 200 RMB, mirtazapine was the most cost-effective; and when the threshold value was over 4 200 RMB, escitalopram was the most cost-effective. In the one-way sensitivity analysis, when we changed the four kinds of drugs costs within a certain range, the results was not changed with the change of venlafaxine’s cost but changed with the other three drugs costs. Conclusion Clinicians may choose the most cost-effective therapy according to patients’ different WTP values. We suggests that health care institutions should encourage the use of escitalopram clinically and provide subsidies for patients so as to increase the overall society benefit.