Respiratory syncytial virus (RSV) infects ~ 90% of young children by the age of 2 yr, with peak rates occurring during 2 to 6 mo of age. Exposure to sidestream (SS) cigarette smoke may increase the incidence or manifestation of an RSV infection. We hypothesized that exposure to SS cigarette smoke would alter the subsequent immune response to RSV infection in neonatal mice. BALB/c mice were exposed to air or 1.5 mg/m³ of SS from d 1 up to 35 d of age. A subset was intranasally infected with 4 x 104 (PFU) of RSV/g body weight on d 7 and rechallenged at 28 d of age. Immune responses were assessed on d 4 and 7 after RSV rechallenge. Both air- and SS-exposed mice responded to RSV rechallenge with neutrophilia and decreased Clara cell secretory protein (CCSP) levels within the lung. However, an increase in bronchoalveolar lavage fluid (BALF) eosinophils, in addition to reduced levels of Th1 cytokines (IFN and IL-12), decreased lung tissue inflammation, and decreased mucus production was observed in SS-exposed mice as compared to air-exposed mice after RSV rechallenge. Ultimately changes in cytokine and inflammatory responses due to SS exposure likely contributed to increased viral gene expression. These results suggest that SS exposure plays a significant role in shaping the neonatal response to RSV infection.