OBJECTIVES: We aimed to investigate the efficacy and safety of human urinary kallidinogenase (HUK) in real-world patients with acute ischemic stroke (AIS). METHODS: AIS patients with prospective follow-up between April 2019 and June 2022 were enrolled in this study. Based on their treatment, the eligible patients were separated into 2 groups: the HUK group and the non-HUK group. Propensity score matching (PSM) analysis was used to reduce the biases from the unequal distribution of initial characteristics. The validated clinical composite scoring system was used to evaluate the neurological recovery. The safety outcomes include stroke recurrence, all-cause mortality, and major complications. RESULTS: A total of 312 patients were enrolled in each of the 2 groups, and there were no significant differences in baseline characteristics between them. After treatment, both groups of AIS patients achieved favorable neurological outcomes. The National Institute of Health Stroke Scale (NIHSS) scores at discharge (3.47±3.41 vs. 4.37±2.85) demonstrated better neurological recovery in the HUK group. At the 90-day assessment, patients in the HUK group exhibited a higher incidence of favorable functional outcome (modified Rankin Scale score of 0 to 2, 74.68% vs. 60.58%), and lower risk of stroke recurrence (2.88% vs. 6.73%). The all-cause mortality (1.60% vs. 2.24%) was not significantly different between both groups. CONCLUSIONS: HUK improved neurological and functional outcomes in patients with AIS in a large real-world population and had an acceptable safety profile.