In this context, the main objective of our study was to examine whether functional polymorphisms in genes coding for crucial mediators of innate immune response, namely, TLR2, TLR4, CD14, CARD8, IL-18, and CD40, can influence COVID-19 clinical severity in a multinational population of patients upon SARS-CoV-2 infection. This evidence concerns the gene CARD8 and COVID-19.