ObjectiveThis study compared the clinical efficacy and safety of argatroban and alteplase in the treatment of acute cerebral infarction. MethodsThis study retrospectively analyzed 131 patients admitted for acute cerebral infarction within 48 h of onset from 1 December 2018 to 1 May 2021. The patients were divided according to treatment (i.e., the argatroban and alteplase groups). The National Institutes of Health Stroke Scale (NIHSS) scores (before treatment, at 24 h, and at 3, 7, and 14 days),14-day response rate, 3-month modified Rankin Scale score (mRS), activities of daily living (ADL) score, prognosis, and adverse events during treatment were compared. ResultsSixty-two and 69 patients were enrolled in the alteplase and argatroban groups, respectively, and both had comparable baseline data. The NIHSS scores of the alteplase group decreased significantly before and after treatment (24 h and at 3, 7, and 14 days), whereas those of the alteplase group decreased most rapidly after 24 h of administration. The argatroban group showed no significant changes in NIHSS score in the first 7 days after treatment until day 14, at which it significantly decreased. Statistically significant differences between the two groups were observed in four points (P < 0.05). The 14-day effectivity rate of alteplase was significantly higher than that of argatroban (83.8% vs. 65.2%; χ2 = 131; P = 0.001). The 3-month mRS, ADL and pre-treatment comparisons were statistically significant in the two groups (P < 0.05), while the inter-group comparison was not statistically significant (P > 0.05). Furthermore, the outcomes at 3 months after treatment in both groups did not vary significantly (alteplase vs. argatroban: 48/62 vs. 51/69; χ2 = 0.217; P = 0.641). Adverse events during treatment included gingival bleeding (two patients), positive fecal occult blood (two patients), and minor intracranial blood ooze (one patient) in the alteplase group, whereas no adverse events (e.g., bleeding and shock) were noted in the argatroban group. ConclusionThe short-term efficacy of argatroban in improving neurological function in patients with acute cerebral infarction was significantly lower than that of alteplase. However, the long-term efficacy at 3 months of treatment was comparably significant to that of alteplase with fewer adverse events.