The objective of our study was to establish whether there is an association between rheumatoid arthritis with extra-articular manifestations (exRA) and anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies in Greeks. A retrospective study of 220 Greek patients with RA, 95 with exRA and 125 without extra-articular manifestations (cRA). Serum anti-CCP2 antibodies and IgM rheumatoid factor (RF) were measured. CCP2(+) were 65.3% of exRA and 58.4% of cRA patients. RF(+) were 69.5% of exRA and 60.0% of cRA patients. Among exRA patients, 37.9% had high serum anti-CCP2 antibody levels (>100 IU/ml) compared to 21.6% cRA patients (p = 0.008). Serositis and pulmonary fibrosis were found to be associated with high levels of anti-CCP2 antibodies (52.9 vs 26.6%, p = 0.02 and 63.6 vs 26.8%, p = 0.008, respectively). Serum RF levels were 265.0 ± 52.0 IU/ml (mean ± SEM) in exRA and 205.1 ± 40.6 (mean ± SEM) in cRA (NS). High serum RF levels (>268 IU/ml) were more likely to have sicca syndrome. In Greek patients with rheumatoid arthritis (RA), high serum anti-CCP2 antibodies are associated with serositis and pulmonary fibrosis. Therefore, anti-CCP2 antibodies have prognostic significance in patients with RA.