Critically ill coronavirus disease 2019 (COVID-19) is characterized by severe cytokine storms, a hyperinflammatory condition intimately related to the development of fatal outcomes . Why some individuals seem particularly vulnerable to severe cytokine storms is still unknown . Primary immunodeficiency (PID) -related genes are inherited factors that dysregulate host inflammatory responses to infection, especially hemophagocytic lymphohistiocytosis (HLH) -related genes, established as contributors to the development of excessive cytokine storms . We analyzed the association between PID gene variants with severe cytokine storms in COVID-19 . We conducted whole-exome sequencing in 233 hospitalized COVID-19 patients and identified four PID gene (UNC13D, AP3B1, RNF168, DHX58) variants were significantly enriched in COVID-19 patients experiencing severe cytokine storms . The total percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical HLH genes, was dramatically higher in high-level cytokine group than in low-level group (33.3 vs. 5.7%, P <0.001). Germline variants in UNC13D and AP3B1 were associated with the development of severe cytokine storms, fatal outcomes in COVID-19 . These findings advance the understanding of individual susceptibility to severe cytokine storms and help optimize the current management of COVID-19.