Matrix metalloproteinases (MMPs) as a family of zinc-dependent endopeptidases have been involved in remodeling the extracellular matrix (ECM) in rheumatoid arthritis (RA). In RA patients synovial fluid and serum include enhanced levels of MMP-3. The 5A/6A polymorphism in the MMP-3 gene promoter can contribute to the severity of RA on account of a higher promoter activity of the 5A allele in vitro. The aim of the study was to associate the 5A/6A polymorphism of the MMP-3 gene with radiographic progression of RA. A total of 128 RA patients according to the ACR criteria were available for the study. Radiographs of both hands, obtained from all RA patients, were scored using the modified Sharp/van der Heijde method and the Steinbrocker method. The total Sharp score (TSS) and the annual radiographic progression rate (TSS/year) were calculated. Significant association with the 5A/6A polymorphism was found between patients with TSS/year <or= 1.00 and those with TSS/year > 1.00 in allelic frequencies (Pa = 0.046) and also in genotype distribution (Pg = 0.04). Compared to other genotypes the prevalence of 5A/5A genotype was lower within patients with TSS/year <or= 1.00 (odds ratio [OR] = 0.2; 95% confidence interval [CI] 0.04-0.85; P = 0.01). Also, in comparison to genotypes 5A/6A and 5A/5A, the prevalence of 6A/6A genotype was higher within patients with nonerosive RA (OR = 2.65; 95% CI 1.03-6.83, P = 0.02). Results obtained in this study provide the evidence of an association of the 5A/6A promoter polymorphism of the MMP-3 gene to the radiographic progression of RA.