Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in nine patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with interindividual variability in COVID-19 phenotypes. Display omitted •Genetic predisposition studies remain limited to investigation of sequencing variants•We used optical genome mapping to investigate large SVs in severe COVID-19 patients•Identified seven rare SVs, with SVs in STK26 and DPP4 as the most promising candidates•Study highlights the potential role of SVs in the pathogenesis of COVID-19 severity Genetic sample; Genomics; Virology