Immunomodulatory treatments targeting excessive host immune responses favorably shifting the course of COVID-19. High doses of calcifediol may reduce the mortality of this infection. To evaluate how a high dose of calcifediol modifies the risk of death in patients hospitalized with COVID-19 during the first outbreaks. A retrospective, observational study to evaluate the relationship between treatment with calcifediol and the risk of death in patients hospitalized with COVID-19 at the "Complejo Hospitalario Universitario de Albacete" (CHUA), Spain, during the months of January to March 2021. Patients were treated with corticosteroids, and some patients also received baricitinib and/or high doses of calcifediol, according to CHUA's therapeutic protocol 2021 for COVID-19. The primary outcome measure was mortality according to calcifediol treatment. A total of 230 patients were included. 25(OH)D levels were measured on admission in 148 patients, showing a high prevalence of vitamin D deficiency [median 25(OH)D: 17.5 ng/mL]. Thirty-four (23%) had severe deficiency (25(OH)D ≤ 10 ng/mL). In the 119 patients (51.7%) who received in-hospital treatment with a high dose of calcifediol, the mortality rate was 12.6% (15 cases, 95% confidence interval [CI], 7.8-19.8%), while in 111 patients who did not receive treatment with calcifediol, the death rate was 23.4% (26 cases, 95% CI: 16.5-32.1%; = 0.039). The odds ratio (OR) in treated vs. untreated patients was 0.47 (95% CI: 0.23-0.95). Among the patients admitted with severe deficiency, 16 received treatment with calcifediol, with a mortality rate of 0.0% (0 cases, 95% CI: 0.0-19.4%), while in the 18 not treated with calcifediol, a death rate of 38.9% was observed (7 cases, 95% CI: 20.3-61.4%; = 0.008). The mortality rate was lower in patients treated with the combination of calcifediol and corticosteroids vs. those treated with corticosteroids alone ( = 0.038) and vs. those treated with corticosteroids and baricitinib ( = 0.033). In the ALBACOVIDIOL study, calcifediol treatment was associated with a lower observed mortality rate in hospitalized patients with COVID-19 treated with corticosteroids (with or without baricitinib), especially in those with severe vitamin D deficiency. Causality cannot be inferred due to the retrospective study design. (Public database: ClinicalTrials.gov, NCT05819918).