Articular involvement is a frequent extrahepatic manifestation of hepatitis C virus (HCV) infection. The distinction between HCV-related polyarthropathy and true RA may be very difficult, especially with recent onset RA before articular damage and erosions develop. The objective of the study is to assess the diagnostic utility of anti-CCP antibodies and compare it with that of rheumatoid factor (RF) in distinguishing between rheumatoid arthritis (RA) and HCV-related polyarthropathy. Anti-cyclic citrullinated peptide (CCP) antibodies and RF were determined in the sera of 30 patients with RA and 22 patients with HCV-related polyarthropathy. Anti-CCP antibodies were positive in 83.3% of patients with RA and in 4.5% in patients with HCV and polyarthropathy. RF was positive in 90% of RA patients and in 81.1% of HCV patients with polyarthropathy. The anti-CCP antibodies showed higher specificity for RA compared with RF (95.4 vs. 18.2%). However, the sensitivity of anti-CCP was comparable to that of RF (83.3 vs. 90%). In conclusions, anti-CCP antibodies are reliable laboratory markers to differentiate between RA and HCV-related polyarthropathy.