Secondhand smoke (SHS) has deleterious respiratory, immune, and nutritional effects in children, but there is little data regarding the effects of SHS exposure in infants with cystic fibrosis (CF). A retrospective chart review was undertaken from 2008 to 2012 of 75 infants with CF. Growth, lung function, Chest CT imaging, and microbiologic characteristics were compared between 4 and 12 months for SHS and non-SHS exposed patients. SHS exposed infants with CF had decreased growth between 4 and 12 months compared to non-SHS exposed infants. SHS exposure was associated with increased bronchodilator responsiveness and air trapping, but no other lung function or radiologic differences. SHS exposure was also associated with increased methicillin resistant Staphylococcus aureus (MRSA) and anaerobic growth on respiratory culture. There was no difference in Pseudomonas aeruginosa between groups. There were no differences in antibiotic use or hospitalizations between the groups. SHS exposure in CF infants is associated with diminished growth, increased air trapping and bronchodilator responsiveness, and propensity to culture MRSA and facultative anaerobic bacteria, suggesting the need for early, aggressive parental smoking cessation interventions to prevent SHS exposure complications.