Objective:To investigate the effect of psychological support during perithrombotic period on post-stroke depression (PSD) in patients with acute ischemic stroke (AIS).Methods:Patients with AIS received intravenous thrombolysis in the Affiliated Lianyungang Hospital of Xuzhou Medical University from January 1, 2021 to July 31, 2021 were enrolled prospectively. The intervention group received one-to-one individual psychological support therapy in the perithrombolytic period on the basis of receiving standard intravenous thrombolytic therapy. At 30 d after onset, Hamilton Depression Scale was used to assess whether PSD occurred. Multivariate logistic regression analysis was used to evaluate the independent influencing factor of PSD. Results:A total of 126 patients with AIS were enrolled, and 86 of them were male (68.25%). Their age was 63.65±10.46 years; 65 were in the intervention group and 61 were in the control group. The incidence of PSD in the intervention group was significantly lower than that in the control group (20.00% vs. 36.07%; χ2=4.049, P=0.044). Multivariate logistic regression analysis showed that psychological intervention (odds ratio [ OR] 0.333, 95% confidence interval [ CI] 0.132-0.838; P=0.020] was an independent protective factor for PSD, while ischemic heart disease ( OR 4.510, 95% CI 1.181-17.217; P=0.028), alcohol consumption ( OR 3.421, 95% CI 1.317-8.888; P=0.012), anticoagulation therapy ( OR 3.145, 95% CI 1.155-8.567; P=0.025) and modified Rankin Scale score before thrombolysis ( OR 1.627, 95% CI 1.142-2.317; P=0.007) were the independent risk factors for PSD. Conclusion:Perithrombolytic psychological support may reduce the incidence of PSD.