To investigate the similarities and differences in clinical features between the sero-negative and sero-positive rheumatoid arthritis (RA) patients. Two hundred and sixty-two RA patients who fulfilled the 1987 ACR RA Classification Criteria were enrolled into this study. They were divided into sero-negative and sero-positive group depending on the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinate peptide (anti-CCP). The clinical features were compared between these two groups. Forty-six (17.6%) RA patients were classified as sero-negative group. The disease onset of sero-negative RA patients was later than that of sero-positive RA patients (52.4 ± 15.9 vs. 47.4 ± 15.5 years, P < 0.05). At the end of the first 2 years after disease onset, bone erosion shown in the hand X-ray occurred in 4 out of 24 (16.7%) patients with sero-negative RA. However, only 5.2% (5/97) patients with sero-positive RA developed bone erosion (P < 0.05). In the sero-positive RA patients, the titer of RF was correlated with swollen joint counts (SJC), tender joint counts (TJC), erythrocyte sedimentation rate (ESR), and disease activity score in 28 joints (DAS28) (P < 0.05), but anti-CCP was not. Sero-negative and sero-positive RA are probably two distinct disease subtypes driven by different mechanisms.