We investigated the association between endogenous vitamin D and the severity of COVID-19 as well as the mechanisms of action of vitamin D supplementation. Vitamin D deficiency and insufficiency were associated with increased severity and unfavourable outcome after 28 days. Vitamin D levels were negatively associated with biomarkers of COVID-19 severity. Vitamin D supplementation after challenge of mice with COVID-19 plasma led to reduced levels of TNFα, IL-6, IFNγ and MPO in the lung, as well as down-regulation of pro-inflammatory pathways as derived from RNA-seq experiments. Thus, vitamin D demonstrates a protective effect against severity and unfavorable outcome in COVID-19, possibly through attenuation of tissue-specific hyperinflammation. Overall design: Differential gene expression analysis using RNA-seq in lungs from mice treated with intravenous injection of plasma from patients with COVID-19 ARDS versus mice treated with intravenous injection of plasma from patients with COVID-19 ARDS plus 1,25(OH)D3 supplementation