The aim of this paper was to study the role of IL6 and IL6R polymorphisms in celiac disease (CD) susceptibility. Because previous literature describes IL-6-related gender differences, sex-stratified analyses were performed. We undertook a case-control study with 374 pediatric CD patients and 853 healthy controls, all white Spaniards, and a family study using an independent sample including 303 trios for replication purposes. Three single-nucleotide polymorphisms tagging most of the variability of the IL6 gene (rs2069827, rs1800795 [-174G/C], and rs2069840) and one functional polymorphism in IL6R (rs8192284, Asp358Ala) were genotyped using TaqMan technology. Case-control comparisons were performed with the chi2 test and family data were analyzed with the transmission disequilibrium test. No association was observed between any tested polymorphism and overall CD. However, after sex stratification, we found that the IL6 promoter variant -174C increases the risk of developing CD specifically in female patients. This effect was observed both in the case-control and in the family studies (considering girls included in both studies vs boys: p = 0.021, odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.03-1.66; and vs controls: p = 0.003, OR = 1.30, 95% CI 1.09-1.55). The functional -174G/C IL6 polymorphism seems to influence CD susceptibility in girls. The gender-specific role of IL-6 in this pathology must be further investigated.