OBJECTIVE: To test for the presence of linkage of the estrogen synthase (CYP19) locus to rheumatoid arthritis (RA) in affected sibling pair (ASP) families. METHODS: Two data sets of RA ASPs (225 ASPs and 107 ASPs) were genotyped for a polymorphic tetranucleotide marker at the CYP19 locus using fluorescence-based semiautomated genotyping technology. Evidence of linkage was assessed by estimating allele sharing (identical by descent) in affected sibling pairs. The effect of this locus was also examined in patient subgroups stratified by sex and by age at disease onset. RESULTS: An increase in allele sharing at the CYP19 locus was observed in the first data set of 225 ASPs (logarithm of odds [LOD] 0.8; P = 0.04). There was also an increase in allele sharing in a second data set, but this did not reach statistical significance (LOD 0.34; P = 0.1). The highest increase in allele sharing was seen in patients with an age at disease onset that was >50 years (LOD 1.1; P = 0.02). CONCLUSION: An increase in allele sharing at the CYP19 locus has been demonstrated in 2 large samples of RA ASPs. The evidence for linkage was strongest in patients with an age at onset that was >50 years, which suggests that this locus may be a susceptibility locus for developing RA later in life. These data provide preliminary evidence that CYP19 may have a role in RA susceptibility