Aim Periodontitis (PD) is influenced by genetic as well as lifestyle and socio-economic factors. Epidemiological studies show that men are at greater risk of severe forms of PD, suggesting interplay between sex and genetic factors. We aimed to systematically analyse patients with aggressive periodontitis (AgP) for gene-sex interactions. Materials and Methods Three hundred and twenty-nine German AgP cases and 983 controls were genotyped with Affymetrix 500K Arrays and were analysed by logistic regression analysis. The most significant gene-sex interaction was replicated in an independent sample of 382 German/Austrian AgP cases and 489 controls. Results Ten single-nucleotide polymorphisms (SNPs) in strong linkage disequilibrium (r2 > 0.85) upstream the gene neuropeptide Y (NPY) suggested gene-sex interaction (p < 5 × 10-5). SNP rs198712 showed the strongest association in interaction with sex (p = 5.4 × 10-6) with odds ratios in males and females of 1.63 and 0.69 respectively. In the replication, interaction of sex with rs198712 was verified with p = 0.022 (pooled p = 4.03 × 10-6) and similar genetic effects. Analysis of chromatin elements from ENCODE data revealed tissue-specific transcription at the associated non-coding region. Conclusion This study is the first to observe a sexually dimorphic role of alleles at NPY in humans and support previous genome-wide findings of a role of NPY in severe PD.