BACKGROUND: Severe respiratory syncytial virus (RSV) infection in neonate has been reported as a risk factor for the development of allergic asthma or early transient wheezing. RSV can induce reinfection by the same strain. Reinfection after neonatal RSV infection can induce eosinophilic inflammation and aggravate airway hyperresponsiveness (AHR) in a BALB/C mouse model. OBJECTIVE: We evaluated whether cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) administration at initial RSV infection could prevent the aggravation of AHR and eosinophilic inflammation with repeated RSV infection in a mouse model. Method: Mice were infected shortly after birth and were reinfected 5 weeks later by the intranasal administration of RSV (106 pfu) and followed by the assessment of airway function, airway inflammation, and lung histopathology. Phosphorothioate CpG (1,826s; 2 mcg/mouse) was also administered intranasally 2 days after initial RSV infection. RESULT: Repeated RSV infection induced methacholine (Mch) AHR, eosinophilic inflammation and goblet cell hyperplasia in the control ODN group. CpG ODN administration at initial RSV infection attenuated Mch AHR and eosinophilic inflammation, and decreased levels of IL-13 and IL-5, but increased IFN-gamma in BAL fluid and RSV- IgG2a in sera. CONCLUSION: These findings suggest that CpG ODN can be used to prevent of airway allergic inflammation by RSV reinfection.