BACKGROUND Vitamin D deficiency is common in patients with cystic fibrosis (CF), and guidelines recommend 25-hydroxyvitamin D (25OHD) levels ≥ 30 ng/mL. This threshold was selected because serum parathyroid hormone (PTH) rises in healthy individuals when the 25OHD level falls below 30 ng/mL. PTH levels > 50 pg/mL are associated with an increased risk of bone loss. However, the relationship between 25OHD and PTH has not been studied in CF. We sought to determine the appropriate goal 25OHD level in patients with CF by identifying the level below which the risk of PTH > 50 pg/mL begins to increase. METHODS Levels of 25OHD and PTH in 216 individuals with CF were collected prospectively. Individuals with 25OHD < 30 ng/mL were treated with vitamin D2, and levels were reevaluated. RESULTS Mean 25OHD level was 25.7 ± 12.4 ng/mL, and mean PTH level was 46.7 ± 25.9 pg/mL. In 63% of individuals, 25OHD level was < 30 ng/mL, and in 38.0% it was ≤ 20 ng/mL. Low 25OHD levels were significantly associated with elevated PTH levels, with a mean PTH of 53.1 ± 29.8 pg/mL for 25OHD level 0 to 19 ng/mL; 51.1 ± 30.7 pg/mL for 25OHD level 20 to 29 ng/mL; 38.4 ± 16.4 pg/mL for 25OHD level 30 to 39 ng/mL; and 37.2 ± 16.4 pg/mL for 25OHD level ≥ 40 ng/mL (P = .006). We assessed the sensitivity of different 25OHD thresholds to identify individuals meeting the goal of a PTH level < 50 pg/mL to reduce the risk of bone loss. To obtain 90% sensitivity, a 25OHD level ≥ 35 ng/mL was required. Strikingly, 23% of individuals with 25OHD levels 30 to 34 ng/mL still had a PTH level > 50 pg/mL. This decreased to 14% for 25OHD level ≥ 35 ng/mL. CONCLUSIONS Inadequate serum 25OHD levels are common in adults with CF and are associated with elevated PTH levels. Aiming to maintain 25-OHD levels ≥ 35 ng/mL in individuals with CF decreases the risk of having a PTH level associated with secondary hyperparathyroidism and bone loss.