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Background Evidence exists that exposure to high levels of microbial agents such as endotoxin in the farm environment decreases the risk of atopic sensitization. Genetic variation in innate immunity genes may modulate the response to microbial agents and thus influence susceptibility to asthma and atopy. Objective To study potential associations between single nucleotide polymorphisms (SNPs) in CD14, Toll-like receptor 2 (TLR2), and TLR4 genes, and atopy and new-onset asthma in young farmers. Methods A nested case–control study was conducted within a cohort of 1901 young Danish farmers. We genotyped 100 new-onset asthma cases and 88 control subjects for three CD14 SNPs, three TLR2 SNPs, and two TLR4 SNPs. Atopy at baseline (defined as a positive skin prick test to one or more common inhalant allergens) was found in 17 asthma cases (17.0%) and in 17 controls (19.3%). Results The CD14/−260T allele was significantly associated with less atopy [odds ratio (OR) 0.39; 95% confidence interval (CI) 0.21–0.72, additive genetic model], whereas the CD14/−651T allele was positively associated with atopy (OR 2.53; 95% CI 1.33–4.80). Similar results were obtained by haplotype analysis. Stratified analysis by farm childhood showed stronger effects of both CD14 SNPs on atopy among farmers who were born and raised on a farm, although no significant interaction was found. No associations between CD14, TLR2, or TLR4 genotypes and new-onset asthma were found. Conclusion The CD14/−260 and CD14/−651 promoter polymorphisms are associated with atopy prevalence among young adults exposed to farm environments. [ABSTRACT FROM AUTHOR]