Complicated skin and skin structure infections (cSSSIs) are characterized by infections with gram-positive or gram-negative aerobic or anaerobic bacteria, as well as by a polymicrobial etiology. These invading microorganisms are recognized by pattern-recognition receptors (PRRs) of the innate immune system. This study assessed whether genetic variation in genes encoding PRRs influences the susceptibility to cSSSIs.A total of 318 patients with cSSSI and 328 healthy controls were genotyped for 9 nonsynonymous single-nucleotide polymorphisms (SNPs) in PRR genes coding for Toll-like receptors (TLRs) 1, 2, 4, and 6; NOD-like receptor 2; and the signaling adaptor molecule TIRAP. Associations between susceptibility to cSSSIs and a SNP were investigated by means of logistic regression models. In an additional cohort of 74 healthy individuals in whom the same SNPs were genotyped, peripheral blood mononuclear cells (PBMCs) were obtained and stimulated with Staphylococcus aureus. Interleukin 6 concentrations were determined in supernatants by enzyme-linked immunosorbent assay to determine the correlation between genotypes and levels of IL-6 secretion.In the genetic association analysis, polymorphisms in TLR1 (S248N and R80T), TLR2 (P631H), and TLR6 (P249S) were associated with an increased susceptibility to cSSSIs. No association with susceptibility to cSSSIs was observed for polymorphisms TLR2 (R753Q), TLR4 (D299G and T399I), NOD2 (P268S), and TIRAP (S180L). In the functional analysis, individuals bearing the TLR1 248N or 80T allele showed lower IL-6 secretion upon stimulation with S. aureus.Polymorphisms in TLR1, TLR2, and TLR6 are associated with increased susceptibility to cSSSIs. For TLR1, impaired proinflammatory cytokine production due to the polymorphism is most likely the mechanism mediating this effect.