Objective To analyze the influencing factors for the incidence and severity of post-stroke depression (PSD) in patients with acute cerebral infarction (ACI) treated by intravenous thrombolysis with alteplase.Methods Three hundred and seventy-five eligible patients with ACI who were admitted to our hospital from February 2015 to January 2017 were enrolled as research subjects. All patients were divided into thrombolysis group (n=190) and non-thrombolysis group (n=185) according to whether thrombolytic therapy was adopted. The development and severity of PSD were evaluated using HAMD-17 scores after 6 months of follow-up. In the meantime, the clinical data were collected by a self-made questionnaire, and the association between influencing factors and the development and severity of PSD was analyzed.Results There were 130 cases of PSD in 375 patients with ACI, in which 47 cases were in the thrombolysis group (27 cases of mild PSD, 16 cases of moderate PSD, and 4 cases of severe PSD), and 83 cases were in the non-thrombolysis group (43 cases of mild PSD, 28 cases of moderate PSD, and 12 cases of severe PSD). The incidence (χ²=6.320, P=0.021) and severity (Z=-2.151, P=0.032) of PSD were significantly different between the two groups. The nursing staff (r=-2.105, P=0.018), mRS score (r=1.810, P=0.018), and whether or not to adopt thrombolytic therapy (r=-1.866, P=0.012) were influencing factors for the development of PSD. The nursing staff (χ²=14.476, P=0.001) and mRS score (t=3.876, P=0.000) had a significant effect on the severity of PSD. The nursing staff had a significant effect on the severity of PSD in the non-thrombolytic group (χ²=6.856, P=0.014); the mRS score had a significant effect on the severity of PSD in both the thrombolysis group (t=2.331, P=0.022) and the non-thrombolysis group (t=2.990, P=0.009).Conclusions Intravenous thrombolysis with alteplase can reduce the incidence and severity of PSD. The nursing staff (family members) and low mRS score are protective factors for PSD.