BACKGROUND: Rheumatoid arthritis (RA) is a persistent autoimmune disorder that impacts the joints, leading to a reduction in physical function and a decline in overall well-being. UCMA is a vitamin K-dependent protein that plays a role in some human diseases, including osteoarthritis and cardiovascular disorders. Nevertheless, the possible role of UCMA in the pathogenesis of RA remains unclear. Therefore, we aimed to investigate the expression of UCMA in serum samples of patients with RA, its relationship with disease activity and some blood markers. METHODS: The current study included 98 RA patients and 24 healthy individuals. Serum UCMA, COMP, TNF-α, and IL-6 levels were measured using enzyme-linked immunosorbent assay. RESULTS: Serum UCMA, COMP, TNF-α, and IL-6 expressions were significantly increased in RA patients compared to healthy controls (p < 0.05). The ROC curve analysis demonstrated that blood UCMA, COMP, TNF-α, and IL-6 levels had the capability to differentiate between patients with RA and healthy controls (p < 0.05). UCMA was positively correlated with certain laboratory indicators, such as COMP, TNF-α, IL-6, CRP, and CCP. CONCLUSION: Here, we report for the first time that UCMA may reflect cartilage degeneration and inflammatory changes in RA patients. Furthermore, UCMA could be employed as a predictive or diagnostic marker in the clinical practice of RA.