Matrix metalloproteinases (MMPs) are the proteases responsible for the destruction of cartilage in rheumatoid arthritis (RA) patients; especially the role of MMP-3 in RA has been highlighted from both pathophysiological studies and clinical studies. However, the role of serum MMP-3 in a large observational cohort of RA patients has not been well demonstrated. In a large observational cohort of RA patients in our Institute (IORRA, October 2000-October 2005, n=3834-5049/phase), disease activity and functional status were routinely assessed biannually. In October 2001, serum MMP-3 was measured in 1265 patients in this cohort, and the data of these patients in the subsequent 4 years were analyzed. The functional status of disability was assessed by JHAQ, the verified Japanese version of HAQ. A cut-off point of 121.0 ng/ml (men) and 59.7 ng/ml (women) was used for MMP-3 positive/negative categorization. The baseline data of these 1265 patients include 81.5% women, mean age 57.9, mean duration 11.1 years, and 71.7% of patients were rheumatoid factor (RF)-positive. Serum MMP-3 levels at the baseline (195.1+227.9 ng/ml) were weakly correlated with C-reactive protein (CRP), but qualitative elevation of serum MMP-3 using cut-off points correlated significantly with corticosteroids use, DAS28, CRP, erythrocyte sedimentation rate, JHAQ, or other markers for the disease activity, but not with age or the disease duration. Thus, elevation of serum MMP-3 level represents the disease activity of RA patients regardless of age or the disease duration. In the longitudinal analysis, the slope of JHAQ progression in patients with MMP-3 positive and RF positive, MMP-3 positive and RF negative, MMP-3 negative and RF positive and MMP-3 negative and RF negative were 0.0179, 0.0162, 0.0156, and 0.0119, respectively, indicating that JHAQ increased most progressively in RA patients with MMP-3 positive and RF positive patients, although statistically apparent differences were not identified. In 502 female patients without talking corticosteroid, patients with MMP-3 positive and RF positive were statistically more progressive in the disability than patients with MMP-3 negative and RF negative. In conclusion, elevation of serum MMP-3 in RA patients is an indicator of inflammation, and together with RF, elevation of serum MMP-3 is a predictive marker for the progression in disability especially in female patients without corticosteroid.