Background: According to the hygiene hypothesis prenatal and early postnatal exposure to environmental endotoxin may be protective against atopy and asthma development (by inducing Th1 type immune response). However, various studies have reported contradictory results. The pathway of endotoxin response involves a complex of innate immunity receptors (CD14, MD2 i TLR4). Genetic variants in CD14, TLR4 and MD2 genes may modify the relationship between endotoxin exposure and asthma Aim: We investigated risk factors for asthma and impact of environmental exposures (endotoxin and house dust mite) on asthma. We evaluated associations between genetic variants in CD14, MD2 and TLR4. In addition, we assesed the effect of endotoxin exposure in the contex of genetic variants. Methods: The study included 837 children 5-18 years old (423 children with asthma and 414 non-asthmatic controls). Data were collected using standardised questionairre. Sensitization was determined by skin prick testing. Dust samples were collected from the child’s mattress, where we measured the endotoxin load (using the Limulus amebocyte lysate test) and Der p1 concentration (using ELISA). We genotyped five variants in CD14 gene, nine in MD2 gene and sixteen in TLR4 by use of mass spectrometry. Results: An increased asthma risk was associated with family history of allergic disease, home dampness, atopy and specific sensitization. Endotoxin exposure was found to have a protective effect against asthma, whereas no such effect was recorded for house dust mite. We found no associations between genetic variants in CD14 and asthma. There were no significant interactions with endotoxin either. Association with asthma was found for variants in MD2 (rs1178659, rs1991262, rs7822407 i rs7838017) and TLR4 (rs1927907 i rs11536889). We observed significant interactions between 4 SNPs in MD2 (rs7822054, rs7822407, rs7838017 i rs11786591), 1 SNP in TLR4 (rs11536889) and endotoxin exposure in relation to asthma. Conclusion: Environmental endotoxin exposure has an important role in pathogenesis of childhood asthma. Genetic variants in the MD2 and TLR4 modify the relationship between endotoxin exposure and asthma.