An elevated pro-inflammatory cytokine response is associated with severe life-threatening symptoms in individuals with Coronavirus Disease-2019 (COVID). The inflammasome is an intracellular structure responsible for generation of interleukin (IL)-1β and IL-18. NALP3, a product of theCIAS1gene, is the rate-limiting component for inflammasome activity. We evaluated if aCIAS142 base pair length polymorphism (rs74163773) was associated with severe COVID. DNA from 93 individuals with severe COVID, 38 with mild COVID, and 98 controls were analyzed for this polymorphism.The 12 unit repeat allele is associated with the highest inflammasome activity. Five alleles, corresponding to 6, 7, 9, 12 or 13 repeat units, divided into 12 genotypes were identified. The frequency of the 12 unit repeat allele was 45.3% in those with severe disease as opposed to 30.0% in those with mild disease and 26.0% in controls (p < 0.0001, severe vs. controls). In contrast, the 7 unit repeat allele frequency was 30.1% in controls as opposed to 14.0% and 12.5% in those with severe or mild disease, respectively (p ≤ 0.0017). We conclude that individuals positive for theCIAS112 allele may be at elevated risk for development of severe COVID due to an increased level of induced pro-inflammatory cytokine production.