Respiratory virus infections are the major cause of acute exacerbations of asthma with human rhinoviruses (RV) accounting for two thirds of infections. Excessive Th2-type responses and deficient anti-viral Th1-type responses generated against RV are associated with exacerbation severity. We recently reported a mouse model of RV infection and showed primary infection was associated with only Th1 responses, however RV infections are frequent throughout life. In a mouse model of repeated RV infection we show the induction of Th2 immune responses, virus-specific IgE and other hallmarks of an allergic response following secondary RV challenge. Both homologous and heterologous RV serotype rechallenges induced eosinophil and lymphocyte infiltration of bronchoalveolar lavage (BAL) and RV-specific serum IgE. The Th2 cytokine IL-4 was detected in BAL 1 day after secondary RV infection, the eosinophil survival/activation factor IL-5 and the chemotactic factor eotaxin were detected in BAL prior to eosinophil cellular infiltration. These results suggest that a Th2-biased immune response generated following repeated RV infection in vivo could contribute to the pathogenesis of asthma exacerbations. With this model it will be possible to dissect out the molecular mechanisms of Th2-biased immune responses to RV and their role in the pathogenesis of RV-induced acute asthma exacerbations.