Here, we have shown, in vitro and in the setting of COVID-19 hospitalized patients, that VitD's anti-viral mechanism can be linked to its ability to increase host type I IFN immunity by increasing the activities of RIG-1/MDA-5 signaling, JAK-STAT pathway, and the resultant IFN α/β signaling and ISGs production. This evidence concerns the gene RIGI and COVID-19.