Background: Patients with cystic fibrosis (CF) who are listed for lung transplantation may require mechanical ventilatory support before transplant. Although CF is a risk factor for poor outcomes in adults, no data currently exist pertaining to pre-transplant ventilatory support in children with CF. Methods: In a retrospective cohort study, we reviewed the medical records of 18 consecutive CF patients transplanted at St. Louis Children's Hospital (SLCH) who required mechanical ventilation before lung transplantation. Controls included patients transplanted at SLCH who were not mechanically ventilated before transplant and were matched for underlying diagnosis, gender, age, type of transplant (cadaveric vs living donor) and year of transplant. Results: Ventilated and non-ventilated patients were similar in their pre-transplant characteristics (weight, height and body mass index) and ischemic and bypass times. However, patients ventilated before transplantation had significantly worse immediate post-transplant outcomes, including early graft dysfunction (p = 0.012), prolonged mechanical ventilation (34.1 vs 5 days, p = 0.009), prolonged stay in the pediatric intensive care unit (35.4 vs 8.1 days, p = 0.01), longer time to hospital discharge (38.4 vs 21.3 days, p = 0.033), and worse 1-year mortality after transplant (221.6 vs 335.2 days, p = 0.021). Among ventilated patients, length of pre-transplant ventilation did not affect post-transplant outcomes (length of ventilation, p = 0.92; length of stay in the pediatric intensive care unit, p = 0.68; time to hospital discharge, p = 0.46; and 1-year mortality rate, p = 0.25). Conclusions: This is the first report in pediatric patients with CF demonstrating that mechanical ventilation before lung transplant is a predictor of poor short-term outcomes, including 1-year-survival, after transplant. Length of pre-transplant ventilatory support does not appear to impact outcomes.