Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease is controversial. The aim of this study was to investigate the role of vitamin D receptor gene (VDR) in rheumatoid arthritis (RA). Three polymorphisms for VDR gene FokI T\backslashtextgreaterC (rs 10735810), BsmI A\backslashtextgreaterG (rs 1544410) and TaqI C\backslashtextgreaterT (rs 731236) were genotyped in 100 RA French nuclear families (set 1) and 100 additional French nuclear families for replication (set 2). The association analysis was performed using comparison of alleles frequencies (AFBAC), transmission disequilibrium test and genotype relative risk. Our results revealed a significant difference of F allele of FokI polymorphism between transmitted and nontransmitted frequencies (P = 0.01) in set 1. Furthermore, the F/F genotype was more frequent in RA patients compared to controls (P = 0.01) in set 1. The replication in set 2 showed similar patterns of transmission with a nonsignificant association. Association with FokI was found to be significant when the two sets were combined (P = 0.006). These data suggest that the F allele and F/F VDR genotype are associated with RA. The mechanisms by which distinct receptor variants might confer disease susceptibility remain to be elucidated. © 2005 Nature Publishing Group. All rights reserved.