Abstract: Vitamin D deficiency is highly prevalent, and recent evidence suggests a possible association between vitamin D deficiency and various health conditions. The aim of this study was to assess monthly calcifediol treatments for vitamin D deficiency (or biweekly, if the deficiency was severe) in a young adult population with no associated comorbidities. This multicentre phase I trial started with a four month open-label treatment phase (TP) that included 101 participants (65% women with mean age 29.8 years). Eighty-two percent of the subjects (79/96) achieved 25(OH)D levels within the target range (20?60 ng/mL) by the end of the TP, and they were subsequently randomised and subjected to a double-blind, placebo-controlled, five month follow-up phase (FP). At the end of the FP, 89% of participants maintained vitamin D levels of >20 ng/mL with calcifediol, versus 49% with placebo (p < 0.001). Subjects receiving monthly calcifediol during both phases (n = 32) maintained 25(OH)D levels >20 ng/mL, whereas those on the placebo during the FP (n = 38) exhibited deficiency levels of 25(OH)D by the end of the study. No clinically relevant changes in bone metabolism parameters or toxic 25(OH)D levels were observed, and no serious adverse events were reported throughout the study. Calcifediol is a safe and effective treatment for vitamin D deficiency in the young adult population, but long-term use may be required to sustain optimal 25(OH)D levels.