Asthma is a heterogeneous chronic pulmonary disease that develops due to the interaction of genetic and environmental factors. This study aimed to investigate the polymorphisms of CTLA4(SNP-318C > T, SNP + 49A > G) and FCεRIα(SNP-344T > C) genes in asthmatic patients in Southwest Iran. The study enrolled 200 patients with asthma of Arab and Bakhtiary descent and 200 healthy controls, where asthmatic patients and healthy controls were selected based on a spirometry test. Genomic DNA from whole blood samples using the TaqMan assay was used to study the genotypes of patients and healthy controls.The results indicated no statistically significant difference between cases and controls for the SNP-344C > T of the FCεR1α gene and the SNP + 49A > G, SNP-318C > T of the CTLA4 gene. There was a significant correlation between the CTLA4-318C > T allele frequency in both the case and control groups (OR = 1.83; 95%CI, 1.14-2.94; P = 0.01). We stratified genotypes according to age, gender, ethnicity, and smoking status and discovered a significant suggestive association between the SNP + 49A > G of the CTLA4 gene and smoking. Additionally, SNP + 49A > G was found to be associated with gender and age. The results indicated that the SNP-318C > T polymorphism in the CTLA4 gene might contribute to the development of asthma in the studied population. Meanwhile, smoking can exacerbate asthma in individuals with SNP + 49A > G of the CTLA4 gene.Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1964525 .