BACKGROUND: Epidemiological assessments of patients and studies using animal models show that exposure to Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine in early life prevents asthma development. However, little is known about the potential of neonatal BCG vaccination in preventing the development of airway remodeling of asthma. OBJECTIVE: To investigate the effects of multiple BCG vaccinations of neonates on the airway remodeling in mice and the accompanied pulmonary T cell responses. METHODS: BALB/c neonates were vaccinated with BCG 3 times. At 5 and 7 weeks of age, the mice were sensitized and then challenged with aerosolized ovalbumin (OVA) 3 times per week for 8 successive weeks. The extent of airway remodeling and induced pulmonary T cell responses were characterized. RESULTS: Multiple BCG vaccinations of neonates reduced OVA-induced remodeling events, including levels of peribronchial α-smooth muscle actin, peribronchial fibrosis, and airway epithelial mucin accumulation. The BCG vaccinations also decreased peribronchial cells expression of transforming growth factor beta 1 (TGF-β1). In contrast, BCG vaccinations increased the frequency of interferon-gamma (IFN-γ)-producing T cells in the lung and IFN-γ level in BALF, with no effects on pulmonary regulatory T cells and IL-17-producing T cells. CONCLUSIONS: Our data suggest that multiple BCG vaccinations of neonates reduced metrics characteristic of allergen-induced airway remodeling. More importantly, this decrease was not associated with an increased number of pulmonary regulatory T cells but instead correlated with an increase of IFN-γ-producing T cells.