In a study of ICU patients with severe COVID‑19, giving higher doses of vitamin D raised blood vitamin D levels and increased the vitamin D receptor in immune cells, but it did not boost the antimicrobial peptide LL‑37. People who already had higher LL‑37 when they arrived at the hospital were less likely to die, though this link weakened after accounting for other health issues.

Vitamin D receptor [VDR] expression promotes LL37 expression, possibly contributing to host defense. The hypothesis was that an increase in 25 hydroxyvitamin D [25vitD] could lead to enhanced VDR expression and increased LL-37 production, thereby contributing to improved prognosis in critically ill patients. <b>Methods</b>: A nonblinded, randomized controlled trial was conducted. A total of 207 patients admitted to ICU with severe SARS-CoV-2 pneumonia were included and received different doses of cholecalciferol (500 MU, 3 MU/day, no cholecalciferol) during their ICU and hospital stay. 25vitD levels as well as LL37 and monocytes' VDR gene expression were evaluated on admission and after. Clinical evolution, ICU mortality, hospital mortality, and 60-day mortality were evaluated. <b>Results:</b> The median age was 57.7 years and the majority of patients were Caucasian [87.4%] and male [70.5%]. There was a significant difference in 25vitD levels between groups on the third [<i>p</i> = 0.002] and seventh [<i>p</i> &lt; 0.001] days. Patients supplemented with 500 MU of cholecalciferol had a very significant increase in monocytes' VDR gene expression and showed a better clinical evolution in the ICU, with a significant correlation to evolution factors. Higher LL37 on admission had a significant negative association with hospital and ICU mortality, lost after adjustment for comorbidities to a nearly significant association with ICU, hospital, and 60-day mortality. <b>Conclusion</b>: Supplementation with higher doses of cholecalciferol may contribute to a significant increase in 25vitD levels but not in LL37 levels. Higher LL37 levels on admission may be related to a decrease in ICU, hospital, and 60-day mortality. VDR gene expression in monocytes is much higher in patients supplemented with higher doses of cholecalciferol.