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Objective: This paired case-control study aimed to evaluate the efficacy and safety of remote ischemic conditioning (RIC) in patients with acute cerebral infarction (CI) and explore potential serological markers of RIC. Methods: Patients with acute CI (<72 h) were matched 1:1 according to age, sex, and CI conditions and were divided into the RIC group and the control group. The RIC group received RIC intervention for 7 days on top of routine treatment, while the control group received a sham RIC. The curative effects and adverse reactions were observed. Result: A total of 66 patients (mean age 60.00 ± 11.37 years; mean time of acute CI onset 32.91 ± 17.94 h) completed the study. The National Institute of Health stroke scale score on day 7, modified Rankin Scale scores on day 7 and day 90 were significantly lower than the baseline in the RIC group (P < 0.001, P = 0.003, P = 0.004, respectively) but not in the control group (P = 0.056, P = 0.169, P = 0.058, respectively). RIC was well-tolerated, and no adverse events were reported. Both plasma hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor increased in the RIC group from day 0 to day 7, while they decreased in the control group. The changes in plasma HIF-1α in the RIC group were statistically different from those in the control group (P = 0.006). Conclusion: Early and short-term RIC treatment was well-tolerated and effective in improving the prognosis in acute CI. HIF-1α can be recognized as a biomarker for evaluating the efficacy of RIC treatment.