Type 1 diabetes (T1D) is an autoimmune disease mediated by T-helper (Th) cells. Additionally, the immune system regulator vitamin D, exerts its modulatory effects through the vitamin D receptor (VDR) expressed in Th cells. Furthermore, several genetic variants in the VDR gene including the VDR FokI (rs10735810) polymorphism have been implicated in T1D susceptibility in some Caucasian populations. Aim of the present study was to investigate the possible functional role of the VDR FokI gene polymorphism in Th cells from T1D patients and healthy controls (HC).Isolated Th cells from 23 HC and 20 T1D patients were stimulated for 72h with 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). After in vitro culture CD3(+)CD4(+) (CD4(+)) Th cell subsets were characterized by flow cytometry and gene expression of VDR was measured by Taqman assay. Finally, the VDR FokI polymorphism was genotyped.Significant lower VDR gene expression was observed in non-stimulated and 25(OH)D3 stimulated Th cells from T1D compared to HC (p=0.04 and p=0.005, respectively). In addition, by stratifying subjects into VDR FokI genotypes, significant lower percentage of CD4(+) cells was observed in 25(OH)D3 and 1,25(OH)2D3 stimulated Th cells from T1D patients carrying the "FF" genotype compared to those with the genotypes "Ff/ff" (p=0.02 and p=0.05, respectively). Moreover, looking at vitamin D effects according to VDR FokI genotypes, CD4(+) cells were significantly down-regulated by 25(OH)D3 and 1,25(OH)2D3 only in T1D "FF" carriers (p=0.01 and p=0.02; respectively).According to these results, T1D patients carrying the "FF" genotype with an adequate vitamin D therapy may benefit from a more balanced T cell immunity. However, further research is needed to confirm these premilinary findings and to elucidate functional mechanisms of genetic variation in the vitamin D system. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.