The aim of this study was to test in a large European population the previously reported association of CD226 gene rs763361/Gly307Ser with SSc, and to analyze, for the first time, the role of two additional polymorphisms, rs34794968 and rs727088, and the effect of CD226 rs763361-rs34794968-rs727088 haplotype in SSc. Here, CD226 is linked to systemic sclerosis.