Staphylococcus aureus (S. aureus) can cause life-threatening infections. Human susceptibility to S. aureus infection may be influenced by host genetic variation. A genomewide association study (GWAS) in a large health plan-based cohort included biologic specimens from 4701 culture-confirmed S. aureus cases and 45344 matched controls; 584,535 single nucleotide polymorphisms (SNP) were genotyped on a European-specific array. Coverage was increased by imputation of >25 million common SNPs using 1000 Genomes Reference panel. In addition human leukocyte antigen (HLA) serotypes were also imputed. ?Logistic regression assuming an additive genetic model revealed several imputed SNPs [e.g., SNP rs115231074: odds ratio (OR)=1.22, P=1.3 x 10(-10); rs35079132: OR=1.24, P=3.8 x 10(-8)] achieving genome-wide significance on chromosome 6 in HLA Class II region. One adjacent genotyped SNP was nearly genomewide significant (rs4321864 OR=1.13, P=8.8 x 10(-8)). These polymorphisms are located near HLA-DRA and HLA-DRB1 genes. Further logistic regression results where the most significant GWAS SNPs were conditioned on HLA-DRB1*04 serotype showed additional support for the strength of association between HLA Class II genetic variants with S. aureus infection. Our study results provide the first reported evidence of human genetic susceptibility to S. aureus infection.