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Hyperosmolality is increasingly recognized as a factor contributing to severe COVID-19. Recently, a genetic variant near the aquaporin 3 (AQP3) water channel was associated with severe COVID-19 (rs60840586:G, Odds Ratio: 1.07, P=2.5*10). The variant is known to increase gene expression of AQP3 in several organs including the lung (NES = 0.33, P = 4.1 * 10) in GTEx. In this study we investigated 576 patients in the Biobanque Quebecoise de la COVID-19 (BQC-19) with both genetic and clinical data was available. We estimated plasma osmolality using the formula: eOSM = 2*[Na] + 2*[K] + [Urea] + [Glucose]. Using a logistic regression of mortality against eOSM, genotype at rs60840586, sex, age and the first ten genetic principal components we confirm that hyperosmolality is associated COVID-19 mortality (OR = 2.06 [95% CI = 1.62-2.65], P = 9.13*10). Interestingly, we found that the risk of death linked to hyperosmolality is influenced by the AQP3 variant rs60840586:G genotype (OR = 1.95 [95% CI = 1.22-3.28], P = 0.0075). However, the rs60840586 genotype did not independently affect mortality in this cohort. These finding suggest that the body's ability to regulate and accommodate for hyperosmolality may be disrupted by over expression of AQP3, potentially worsening outcomes in COVID-19. Given the role of AQP3 in water transport and homeostasis, further defining the functionality of its variants may provide key insights into COVID-19 severity and guide clinical management strategies, particularly in critically ill patients with hyperosmolality.