Background The effectiveness of current treatment recommendations for vitamin D insufficiency in children with CF is unknown. Therefore, we assessed the effectiveness of vitamin D 2 50,000 IU once daily for 28 days for vitamin D insufficiency. Methods Retrospective chart review of pediatric CF patients from 2006–2008. Vitamin D 2 50,000 IU daily for 28 days was given to patients with 25-OHD < 30 ng/mL and repeat 25-OHD levels were obtained after completion of therapy. Results One hundred forty-seven levels from 97 individuals were assessed. Success of treatment was 54% ( n = 80/147). Seventeen of 39 patients (43%) followed for an additional 6–18 months were able to maintain levels of ≥ 30 ng/mL. Conclusions Vitamin D 2 50,000 IU daily for 28 days was effective in correcting vitamin D insufficiency in approximately 50% of subjects. However, almost half of successfully treated patients were unable to maintain normal 25-OHD levels > 6 months after completion of therapy, implying that this effect is transient.