Background: Rheumatoid Arthritis, (RA) is a chronic inflammatory autoimmune disease with a progressive course requiring early diagnosis and treatment. The value of anti-cyclic citrullinated peptide antibodies (Anti-CCP) in the diagnosis of RA has been shown in several studies. The present study was designed to determine and compare the diagnostic value of Anti-CCP and rheumatoid factor (RF) for RA.Methods: 207 females and 48 males with RA, diagnosed by clinical criteria, with the mean age of 50±13.8 years and 290 non-RA controls with the mean age of 47±14 years were enrolled in the study. Serum samples were taken for assessment of Anti-CCP and RF from all participants.Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-)and their 95% confidence interval (95%CI) were estimated by comparison of patients with controls. Results: In patients with RA, Anti-CCP was positive in 79.2% and RF was positive in 72.1%; and both antibodies were positive in 64.7%, and both negative in 13.3%. 47.8% of seronegative RA was Anti-CCP positive and 7.8% of anti-CCP negative were RF positive.Sensitivity, specificity, PPV, NPV, LR+ and LR- for Anti-CCP in diagnosis of RA were: 79.2%, 94.8%. 93.08%, 83.8%, 13.46 and 0.19 respectively; for RF the respective values were 72.1%, 90.6%, 87.2 %, 78.7%, 6.81, and 0.26. For both Anti-CCP and RF the values were 64.7%, 97.5%, 95.9 %, 75.8%, 26.8and 0.36.Anti-CCP was more diagnostic than RF and both antibodies had more diagnostic values than either of them alone. Anti-CCP yielded a specificity of 89.6% and PPV of 85% for diagnosis of seronegative RA.Conclusion: The findings of this study indicate that anti-CCP has a higher diagnostic performance than RF. It is highly useful in the diagnosis of seronegative RA. In addition, presence of both antibodies is more diagnostic than either of them alone.