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Background The PTPN22 / CSK signalling represents one of the most relevant pathways in the innate immunity, and it has been implicated in the susceptibility to develop a wide number of autoimmune diseases. Objectives To analyse the possible role of different single-nucleotide polymorphisms of the PTPN22 and CSK genes in the predisposition and clinical phenotypes of giant cell arteritis (GCA) in a large Caucasian population. Methods Our study population consisted of 623 patients diagnosed with biopsy-proven GCA and 1,729 healthy controls of Spanish Caucasian origin. Two functional PTPN22 polymorphisms (rs24746601, R620W and rs33996649, R263Q) and two variants of the CSK gene (rs1378942 and rs34933034), previously associated with autoimmunity, were genotyped using specifically designed TaqMan® assays. Results A significant association of the PTPN22 non-synonymous change rs2476601 with GCA susceptibility was yielded after the analysis of the allele frequencies ( P =1.06E-04, OR= 1.62, CI 95% 1.29-2.04). No statistically significant differences between cases and controls of the rest of SNPs analysed were observed. Similarly, when patients were stratified according to specific clinical features of GCA, such as polymyalgia rheumatica (PMR), visual ischemic manifestations (VIM) or irreversible occlusive disease (IOD), only significant differences were found between the case subgroups and the control set for PTPN22 rs2476601 ( P =2.26E-04, OR=1.77 CI 95% 1.30-2.40; P =1.03E-03, OR=1.82 CI 95% 1.27-2.62; P =5.47E-04, OR=2.14 CI 95% 1.38-3.33, respectively). Conclusions Our results clearly suggest that the PTPN22 polymorphism rs2476601 is associated with susceptibility to GCA. Disclosure of Interest None Declared