Objetive A single nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts.Patients and Methods We analyzed ten GWAS genotyped single nucleotide polymorphisms (SNPs) in the IL12RB2 region (2,309 SSc patients and 5,161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080), based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3,344 SSc and 3,848 controls. The most associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1,139 controls from the US.Results After conditional logistic regression analysis of the GWAS data, we selected rs3790567 (P(MH)= 1.92x10(-5) OR = 1.19) as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84x10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82x10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for rs3790567 SNP in IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82x10(-9) OR = 1.17).Conclusion Our data clearly support IL12RB2 genetic association with SSc, and suggest a relevant role of the IL-12 signaling pathway in SSc pathogenesis.