Background: Ankylosing Spondylitis (AS) is a polygenic disorder. CNVs alter the expression of TLR7, T-bet, IL-12B, and FcℽRIIIB genes, potentially contributing to AS development due to their roles in the immune system. Objective: The current study aimed to assess the correlation between AS susceptibility and CNVs of TLR7, T-bet, IL12B, and FcℽRIIIB, as well as their influence on disease activity. Methods: The study involved 42 healthy controls and 72 patients with AS, recruited from Rheumatology and Rehabilitation clinic of Zagazig University Hospitals, Zagazig, Egypt, from 01 November 2023 to 30 October 2024. Sociodemographic, clinical data and blood samples were collected from all participants. Copy number genotyping estimations for TLR7, T-bet, IL12B, and FcℽRIIIB genes were performed using SYBR Green real-time PCR. Results: Of 72 cases aged 19 to 52 years, 47(65.2%) were men and 25(34.8%) were women. Controls included 42 participants aged 27 to 55 years, 22(52.4%) men and 20(47.6%) women. Higher IL12b and FcℽRIIIB gene copy numbers were significantly associated with a higher risk of AS (p 0.001, OR 3.8, 95% CI 1.7-8.07, and p <0.001, OR 5.5, 95% CI 2.31-13.08, respectively). While T-bet and TLR7 gene CNVs did not show a significant association with AS risk. No significant association was observed between the studied CNVs and AS activity. Conclusion: High copy numbers of IL12B and FcℽRIIIB genes may be associated with increased risk of AS. However, no significant correlation was found between AS risk and TLR7 or T-bet CNVs.