OBJECTIVE： To compare the therapeutic efficacy and safety of sertraline and paroxetine in the treatment of post stroke depression. METHODS： The information of 91 patients with post stroke depression were analyzed retrospectively and divided into observation group （42 cases） and control group （49 cases） according to therapy plan. Based on routine treatment， observation group was given Sertraline hydrochloride tablet orally with initial dose of 50 mg at first week， once a day， increasing by 50 mg each week， no more than 200 mg. Control group was given Paroxetine tablet with initial dose of 10 mg， once a day， increasing by 10 mg each week， no more than 40 mg. Treatment course of 2 groups lasted for 2 months. Clinical efficacies of 2 groups were observed. NIHSS score， MMSE score， HAMD score， the serum levels of 5-HT， BDNF and S100β were observed before and after treatment， and the correlation of serum levels of 5-HT， BDNF and S100β with HAMD score were evaluated in observation group after treatment； the occurrence of ADR was recorded. RESULTS： The total response rate of observation group （90.48％） was significantly higher than that of control group （73.47％）， with statistical significance （P＜0.05）. After treatment， NIHSS score， HAMD score and S100β level of 2 groups were significantly lower than before treatment， and HAMD score and S100β level of observation group were significantly lower than those of control group. MMSE score， serum levels of 5-HT and BDNF in 2 groups were significantly higher than before treatment， and the observation group was significantly higher than the control group， with statistical significance （P＜0.05）. There was no statistical significance in NIHSS score between 2 groups （P＞0.05）. The serum levels of 5-HT and BDNF were negatively correlated with HAMD score in observation group after treatment， and the level of S100β was positively correlated with HAMD score. There was no statistical significance in the incidence of ADR between 2 groups （P＞0.05）. CONCLUSIONS： Based on routine treatment， therapeutic efficacy of sertraline is significantly better than that of paroxetine in the treatment of post stroke depression， and can improve cognitive function and depression. The two drugs are similar in improving nerve function and mental state， safety.