AbstractSevere COVID‐19 has a poor prognosis, while the genetic mechanism underlying severe COVID‐19 remains largely unknown. We aimed to identify genes that are potentially causally associated with severe COVID‐19. We conducted a summary data‐based Mendelian randomization (SMR) analysis using expression quantitative trait loci (eQTL) data from 49 different tissues as the exposure and three COVID‐19‐phenotypes (very severe respiratory confirmed COVID‐19 [severe COVID‐19], hospitalized COVID‐19, and SARS‐CoV‐2 infection) as the outcomes. SMR using multiple SNPs was used as a sensitivity analysis to reduce false positive rate. Multiple testing was corrected using the false discovery rate (FDR) q‐value. We identified 309 significant gene‐trait associations (FDR q value < 0.05) across 46 tissues for severe COVID‐19, which mapped to 64 genes, of which 38 are novel. The top five most associated protein‐coding genes were Interferon Alpha and Beta Receptor Subunit 2 (IFNAR2), 2′‐5′‐Oligoadenylate Synthetase 3 (OAS3), mucin 1 (MUC1), Interleukin 10 Receptor Subunit Beta (IL10RB), and Napsin A Aspartic Peptidase (NAPSA). The potential causal genes were enriched in biological processes related to type I interferons, interferon‐gamma inducible protein 10 production, and chemokine (C‐X‐C motif) ligand 2 production. In addition, we further identified 23 genes and 5 biological processes which are unique to hospitalized COVID‐19, as well as 13 genes that are unique to SARS‐CoV‐2 infection. We identified several genes that are potentially causally associated with severe COVID‐19. These findings improve our limited understanding of the mechanism of COVID‐19 and shed light on the development of therapeutic agents for treating severe COVID‐19.