OBJECTIVE： To observe therapeutic efficacy and safety of paroxetine combined with flupentixol melitracen in the treatment of post-stroke major depressive disorder （PSMDD）. METHODS： 120 PSMDD patients were randomly divided into group A （40 cases）， group B （40 cases） and group C （40 cases）. All patients received routine stroke treatment； group A was additionally given Paroxetine hydrochloride enteric-coated sustained-release tablet 25 mg orally， once a day； group B was additionally given Flupentixol melitracen tablet 20 mg orally twice a day； group C was additionally given Paroxetine hydrochloride enteric-coated sustained-release tablet （same usage and dosage as group A）+flupentixol melitracen （same usage and dosage as group B）. Three groups were treated for 28 d. Clinical efficacies of 3 groups were observed as well as NIHSS， ADL， HADM， SS-QOL score， hospitalization stay and the occurrence of ADR. RESULTS： Total response rate of group C was significantly higher than those of group A and B； hospitalization day was significantly less than those of group A and B， with statistical significance （P＜0.05）； there was no statistical significance between group A and B （P＞0.05）. There was no statistical significance in the incidence of ADR among 3 groups （P＞0.05）. Before treatment， there was no statistical significance in NIHSS， ADL， HADM， SS-QOL score among 3 groups （P＞0.05）. After 10， 28 d of treatment， NIHSS， HADM， SS-QOL score of 3 groups were significantly lower than before，above indexes were decreased gradually as time， and the group C were lower than the group A and B； ADL score of 3 groups were significantly higher than before， this index was increased gradually as time， and the group C were lower than the group A and B with statistical significance （P＜0.05）； there was no statistical significance between group A and B （P＞0.05）. CONCLUSIONS： Based on routine treatment， paroxetine combined with flupentixol melitracen  in the treatment of PSMDD can relieve neurologic function injury， improve depression condition and the quality of life without increasing the occurrence of ADR.