Background: CYP2C19 genetic variation and clinical factors have been proved to be related with clopidogrel resistance (CR) in adults, while the presence of CR in children with Kawasaki disease (KD) was seldom reported. Our objective was to evaluate KD patients' response to clopidogrel treatment and determine whether CYP2C19 gene polymorphisms and laboratory indicators are associated with CR in this population. Methods: This was a prospective and single-center study. We recruited children with KD hospitalized in the cardiology department at the Children's Hospital Capital Institute of Pediatrics between January 2019 and October 2021, and the distribution of the CYP2C19 gene polymorphisms was assessed. According to the light transmission aggregometry (LTA) test results, KD patients who were treated with clopidogrel were divided into CR group and non-CR (NCR) group. We also analyzed the influence of CYP2C19 gene polymorphisms and laboratory indicators on CR in children with KD. Results: (1) A total of 346 children with KD were evaluated for the genotypic and phenotypic distributions of CYP2C19. Loss-of-function (LOF) mutated allele was included in 56.9% of CYP2C19 genotypes, and their corresponding phenotypes were intermediate metabolizers (46.2%) and poor metabolizers (10.7%). (2) The incidence of CR in this study population was 31.4%. The multivariate logistic regression showed that carrying CYP2C19 LOF allele (OR, 3.922; 95%CI, 1.504-10.282; P = 0.005) and high levels of low-density lipoprotein (OR, 1.675; 95%CI, 1.069-2.623; P = 0.024) were independent risk factor for CR, while low levels of high-density lipoprotein (OR, 0.120; 95%CI, 0.020, 0.734; P = 0.022) was an independent protective factor for CR. The area under the receiver operator characteristic curve of the multivariate logistic regression model (including high-density lipoprotein, low-density lipoprotein, and CYP2C19 LOF allele carriers) for predicting CR was 0.769 (95% CI, 0.674-0.863; P < 0.001). The sensitivity and specificity were 70.3 and 74.0%, respectively. Conclusion: Carrying CYP2C19 LOF allele, low levels of high-density lipoprotein, and high levels of low-density lipoprotein were independent risk factors for CR in children with KD in China. This may benefit pediatricians in choosing appropriate individualized antiplatelet therapy.