Background: The most prevalent inflammatory arthropathy in the world is rheumatoid arthritis (RA), a chronic inflammatory autoimmune (AI) disease. As rheumatoid factor (RF) and anti-CCP are unable to diagnose correctly all the patients, recent research raised the possibility that serum connective tissue growth factor (CTGF) could function as a highly sensitive and specific diagnostic biomarker for RA. Objectives: To evaluation of diagnostic value of serum CTGF in RA patients, investigation of the relationships between serum CTGF and RF and anti-CCP, and investigation of the relationships between serum CTGF and disease activity. Subjects and Methods: Four groups were involved in this case-control study: 45 RA cases, 45 OA cases, 45 SLE cases, and 45 healthy controls. ESR, CRP, RF, and anti-CCP laboratory tests were performed on all RA cases. Physical examination for painful and swollen joints, the DAS 28 CRP test, and a history-taking procedure were performed. All subjects underwent testing to determine their serum CTGF levels. Results: The present study found that serum CTGF levels were higher in RA patients than in SLE patients, OA patients and healthy control individuals. The correlation between serum CTGF and rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and DAS-28-CRP was positive. Serum CTGF had a high specificity and sensitivity for RA cases. Conclusion: CTGF could be a possible biomarker for diagnosing RA as well as monitoring disease activity.