Background: There is little consensus on the most efficacious vehicle substance for vitamin D supplements. Fat malabsorption may impede the ability of patients with cystic fibrosis (CF) to absorb vitamin D in an oil vehicle. We hypothesized that vitamin D contained in a powder vehicle would be absorbed more efficiently than vitamin D contained in an oil vehicle in patients with CF. Methods: In this double-blind, randomized controlled trial, hospitalized adults with CF were given a one-time bolus dose of 100,000 IU of cholecalciferol (D3) in a powder-based or oil-based vehicle. Serum D3, 25-hydroxyvitamin D, and parathyroid hormone concentrations were analyzed at 0, 12, 24, and 48 hours posttreatment. The area under the curve for serum D3 and the 12-hour time point were also assessed as indicators of D3 absorption. Results: This trial was completed by 15 patients with CF. The median (interquartile range) age, body mass index, and forced expiratory volume in 1 second were 23.7 (19.9–33.2) years, 19.9 (18.6–22.6) kg/m2, and 63% (37%–80%), respectively. The increase in serum D3 and the area under the curve was greater in the powder group (P = .002 and P = .036, respectively). Serum D3 was higher at 12 hours in the powder group compared with the oil group (P = .002), although levels were similar between groups by 48 hours. Conclusions: In adults with CF, cholecalciferol is more efficiently absorbed in a powder compared with an oil vehicle. Physicians should consider prescribing vitamin D in a powder vehicle in patients with CF to improve the absorption of vitamin D from supplements.