It was investigated whether radiographic osteoarthritis (ROA) is associated with specific haplotypes of the COL2A1 gene. Radiographs of knees, hips, hands, and spine were scored for the presence of ROA in subjects of 55-70 years from a population-based cohort study, the Rotterdam study. Cases had ROA in 3 or more joint groups; controls, from the same population, had ROA in less than 3 joint groups. Allele frequencies of 3 dimorphisms (HaeIII, HindIII, MaeII) and a VNTR polymorphism of the COL2A1 gene were determined. The VNTR allele 14R2 and the HindIII polymorphism showed a significant association. Haplotype analysis of the HaeIII, HindIII and VNTR polymorphisms showed that a specific haplotype (1-2-14R2) is strongly associated with ROA in 3 or more joint groups (OR = 5.3, 95% CI 2.3-12.7). Our results suggest that a specific haplotype of the COL2A1 locus may predispose to generalised ROA.