Objective To compare the clinical efficacy of contact thrombolytic therapy between transradial artery intervention (TRI) and transfemoral artery intervention (TFI) pathways in patients with acute ischemic stroke (AIS). Methods The clinical data of 64 patients with AIS consistent with the indication of arterial thrombolysis in the People's Hospital of Huimin County of Shandong province from January 2010 to October 2017 were treated with arterial contact thrombolysis after exclusion of contraindications, including 42 cases treated with TRI (TRI group) and 22 cases treated with TFI (TFI group), and they were analyzed retrospectively. The differences in success rate of puncture, puncture time, the interval between the sheath set to the artery and the catheter reaching the diseased vessels, the re-canalization rate of occlusive vessels, surgical time, puncture site bleeding and intracranial bleeding complications and clinical outcomes in the patients were compared between the two groups. Results The comparisons of following indicators between the TRI group and TFI group were as follows: success rate of puncture [97.6% (41/42) vs. 100.0% (22/22)], puncture time (minutes: 5.5±2.0 vs. 5.4±2.3), the interval between sheath set to the artery and catheter reaching the diseased vessel (minutes: 6.2±3.8 vs. 6.7±3.9), occlusive vascular re-canalization rate [45.2% (19/42) vs. 40.9% (9/22)], operation time (hours: 1.50±0.38 vs. 1.45±0.32), incidence intracranial bleeding complications [9.52% (4/42) vs. 9.09% (2/22)], and the differences in above indicators in comparisons between the two groups had no statistical significance (all P > 0.05); however, the complication of bleeding at puncture site in TRI group was significantly lower than that in TFI group [0 vs. 22.7% (5/22), P < 0.05]. There was no statistical difference in clinical outcomes between the two groups. Conclusion It is safe and effective to treat patients with AIS by the TRI approach.