Background Integrin β3 ( ITGB3 ) and Toll-like receptor 2 ( TLR2 ) are candidate genes for asthma and sensitization to mold allergens. Integrin β3 forms a complex with TLR2, and this biological interaction is required for the response of monocytes to TLR2 agonists such as fungal glucan. Objective To study whether genetic interaction between single nucleotide polymorphisms (SNPs) in genes encoding the TLR2-ITGB3 complex enhances susceptibility to mold sensitization. Methods Association analysis was conducted in 1243 adults (524 with asthma) who participated in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma. Allergic sensitization to mold allergens was determined by skin prick testing. Association of mold sensitization with 14 ITGB3 SNPs was tested under an additive genetic model. Interaction between ITGB3 SNPs and TLR2 /+596, which was previously shown to be associated with asthma, was studied. Results A positive skin prick test to mold was found in 115 subjects with asthma (22.0%) and in 61 subjects without asthma (8.5%). The ITGB3 rs2056131 A allele was associated with mold sensitization in subjects with asthma with an odds ratio (95% CI) of 0.60 (0.43-0.83; P  = .001). Ten other ITGB3 SNPs were significantly associated with mold sensitization in TLR2 /+596TT subjects with asthma ( P  = .03-.002), whereas much weaker associations were found in carriers of the TLR2 /+596 C allele ( P  = .60-.04). Interaction between TLR2 /+596 and these  ITGB3 SNPs was statistically significant ( P interaction = .05-.001). Conclusion TLR2/+596 genotype may influence the association between ITGB3 SNPs and mold sensitization in adults with asthma.