Objective To investigate the association of the serum level of soluble cluster of differentiation 40 ligand (sCD40L) levels with carotid atherosclerotic plaque in patients with acute cerebral infarction.Methods A total of 108 patients with acute cerebral infarction who were admitted to Department of Neurology, Shengjing Hospital of China Medical University, from May 2018 to May 2019 were enrolled. According to the findings of carotid artery ultrasound, they were divided into non-plaque group and plaque group, and the plaque group was further divided into stable plaque group and unstable plaque group according to the nature of plaque. ELISA was used to measure the serum level of sCD40L, and the association between serum sCD40L level and carotid atherosclerotic plaque was analyzed.Results Compared with the non-plaque group, the plaque group had a significantly higher proportion of patients with hypertension (P=0.026), as well as significantly higher levels of fasting blood glucose (P=0.045), triglyceride (P=0.027), low-density lipoprotein cholesterol (LDL-C) (P=0.005), and sCD40L (P<0.001). Hypertension (odds ratio [OR]=2.598, P=0.028), LDL-C (OR=4.247, P=0.006), and serum sCD40L level (OR=1.079, P=0.009) were independent risk factors for the presence of carotid atherosclerotic plaque in patients with acute cerebral infarction. Compared with the stable plaque group, the unstable plaque group had a significantly higher proportion of patients with hypertension (P=0.031), as well as significantly higher levels of white blood cell count (P=0.002), LDL-C (P=0.003), and serum sCD40L level (P<0.001). In the unstable plaque group, hypertension (OR=2.918, P=0.033) and serum sCD40L level (OR=2.712, P<0.001) were independent risk factors for unstable carotid plaques.Conclusions In patients with acute cerebral infarction, the increase in serum sCD40L level might be associated with the development and progression of carotid atherosclerotic plaque and the instability of carotid plaque.