RSV bronchiolitis and pneumonia in infancy is known to be associated with increased susceptibility to asthma. This phenomenon is characterized by a hyper reactive airway with a predominant Th2 response and a skewed dendritic cell (DC) polarization, which can be modulated by exogenous OPN administration. OPN is an immunomodulatory agent inducing a strong Th1 polarization in RSV infected lungs. In our present study, we used a neonatal mouse model to examine the transcriptional regulation of this immunomodulation in RSV-infected pups. RSV-infected pups were intranasally administered with or without different doses of OPN, and messenger RNA (mRNA) expression of GATA-3 and STAT-6 were examined by PCR and RTPCR methods. At day 3 post-infection, GATA-3 expression was significantly higher in the OPN treated lungs compared to that in the PBS treated lungs, contradicting the enhanced Th1 cytokine responses observed after OPN treatment. Interestingly, an enhanced expression of STAT-6 was also observed at the same time point in the OPN treated and RSV infected pups compared to that in the PBS treated pups. Of note, STAT-6 influences IL4 transcription which has a prominent role in Th2 differentiation. On the other hand, IL-4 instructs DC to promote Th1 differentiation which is STAT-6 dependent. Thus, the transcriptional regulation of OPN-induced immunomodulation is not one-dimensional and will need further investigations into the dynamics of other transcriptional factors (e.g. T-bet and Foxp3) to establish OPN as a novel therapeutic in the prevention of RSV-induced susceptibility to asthma.