The role of Toll-like receptor (TLR) 2 in modulating allergy-induced asthma is contradictory. We investigated the effect of TLR2 gene deletion in a murine model of ovalbumin (OVA)-challenged asthma. TLR2 wild-type (TLR2(+/+)) and TLR2-deficient (TLR2(-/-)) mice were sensitized to soluble OVA antigens and challenged with OVA, and the extent of allergic airways disease was analyzed in both groups of mice at day 8 after being challenged with OVA aerosol. At day 8 post-OVA, TLR2(-/-) mice exhibited significantly lower airway hyperresponsiveness, airway inflammation, and whole lung T-helper type 2 (Th2) cytokine levels compared with the TLR2(+/+) group. TLR2 deletion also significantly reduced mucus cell metaplasia and peribronchial fibrosis in mice at day 8 after challenged by OVA. The p38/AKT/nuclear factor kappaB (NF-kappaB) p65 and phosphate extracellular signal-regulated kinase (ERK)/p38/AKT was decreased in TLR2(-/-) mouse lungs. Thus, during OVA asthma in mice, TLR2 is a major contributor to the maintenance of the adaptive Th2-cytokine-driven inflammatory disorder and ERK/p38 as well as AKT/NF-κB playing a role in it.