In this report, we present an 18-year-old female with severe COVID-19 and features of HLH, who was found to have a rare (0.036%, Genome Aggregation Database) heterozygous STXBP2 (c.1286C > T, p.Ala429Val) missense mutation and defective NK cell killing. The gene discussed is STXBP2; the disease is COVID-19.