Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovial inflammation and progressive joint destruction. Its etiology is multifactorial, involving complex interactions between genetic predisposition, environmental triggers, and immunological dysregulation. Among the candidate genes implicated in RA pathogenesis, PTPN22 (protein tyrosine phosphatase, non-receptor type 22) has emerged as a critical regulator of T-cell receptor (TCR) signaling and a recognized susceptibility locus across diverse ethnic populations. However, data on PTPN22 polymorphism in Central Asian populations, including the Uzbek population, remain scarce. In the present study, we investigated the association of the PTPN22 1858C>T single nucleotide polymorphism (rs2476601) with RA susceptibility in an Uzbek cohort. A total of 118 RA patients, diagnosed according to the 2010 ACR/EULAR classification criteria, and 80 healthy controls of matched ethnicity and socioeconomic background were recruited from rheumatology centers in Uzbekistan. Genotyping was performed using the PCR-RFLP method with XcmI restriction enzyme digestion. Genotype frequencies, allele distributions, and carriage rates were compared between patient and control groups using chi-square and Fisher’s exact tests. Our findings revealed a statistically significant difference in the distribution of PTPN22 genotypes between RA patients and healthy controls (p=0.027). The T allele and CT/TT genotype carriage were found at significantly higher frequency in RA patients compared to controls (OR=2.17, 95% CI: 1.21–3.89; p=0.009), suggesting a meaningful association with RA susceptibility in the Uzbek population. Notably, the CC genotype was significantly associated with higher disease activity as assessed by DAS28 and SDAI scores (p<0.01). The T allele frequency in our cohort (11.4%) was lower than that reported in European populations, reflecting the distinct genetic background of the Uzbek population. This study represents the first investigation of PTPN22 rs2476601 polymorphism in RA patients from Uzbekistan, and supports the role of this variant as a potential genetic marker of RA susceptibility and disease severity in Central Asia.