Objective To compare the efficacy and safety of intravenous thrombolysis in acute ischemic stroke (AIS) with different etiology types.Methods AIS patients who received intravenous thrombolysis with alteplase in our center from Jan. 2016 to Dec. 2020 were retrospectively included, and the clinical data were collected. According to the classification of Trial of Org 10172 in Acute Stroke Treatment (TOAST), the patients were divided into large artery atherosclerosis (LAA) group, small artery occlusion (SAO) group, cardioembolism (CE) group, stroke of other determined etiology (SOE) group and stroke of undetermined etiology (SUE) group. The early effective rate 24 h after treatment, good prognosis rate 90 d after treatment and hemorrhagic transformation rate were compared among different etiology groups. Multivariate logistic regression analysis was used to explore whether TOAST classification was an influencing factor of prognosis 90 d after intravenous thrombolysis.Results A total of 538 AIS patients were enrolled, including 140 (26.0%) patients in the LAA group, 233 (43.3%) in the SAO group, 98 (18.2%) in the CE group, 58 (10.8%) in the SUE group and 9 (1.7%) in the SOE group. It was effective in 210 (39.0%) AIS patients 24 h after intravenous thrombolysis, including 56 (40.0%) patients in the LAA group, 85 (36.5%) in the SAO group, 41 (41.8%) in the CE group, 26 (44.8%) in the SUE group and 2 (22.2%) in the SOE group, showing no significant difference (P=0.596). There were 443 (82.3%) AIS patients with good prognosis (modified Rankin scale score of 0-2) 90 d after treatment, including 108 (77.1%) patients in the LAA group, 201 (86.3%) in the SAO group, 82 (83.7%) in the CE group, 45 (77.6%) in the SUE group and 7 (77.8%) in the SOE group, showing no significant difference (P=0.147). Thirty-six (6.7%) AIS patients had hemorrhagic transformation after treatment, including 10 (7.1%) patients in the LAA group, 11 (4.7%) in the SAO group, 11 (11.2%) in the CE group, 3 (5.2%) in the SUE group and 1 (11.1%) in the SOE group, showing no significant difference (P=0.209). Multivariate logistic regression analysis showed that TOAST classification was not a prognostic factor of AIS patients 90 d after intravenous thrombolysis.Conclusion There are no significant differences in the efficacy or safety of intravenous thrombolysis in AIS patients with different etiology types.