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Background: Systemic inflammation has been associated with severe coronavirus disease 2019 (COVID-19) disease and mortality. Hyponatremia can result from inflammation due to non-osmotic stimuli for vasopressin production.Methods: We prospectively studied 799 patients hospitalized with COVID-19 between March 7 and November 7, 2020, at Hospital Posadas in Buenos Aires, Argentina in order to evaluate the association between hyponatremia, inflammation, and its impact on clinical outcomes. Admission biochemistries, high-sensitivity C-reactive protein (hsCRP), ferritin, patient demographics, and outcome data were recorded. Outcomes (within 30 days after symptoms) evaluated included ICU admission, mechanical ventilation, dialysis-requiring acute kidney injury (AKI), and in-hospital mortality. Length of hospital stay (in days) were evaluated using comprehensive data from the EHR.Results: Hyponatremia (median Na = 133 mmol/L) was present on admission in 366 (45.8%). Hyponatremic patients had higher hsCRP (median 10.3 [IR 4.8–18.4] mg/dl vs. 6.6 [IR 1.6–14.0] mg/dl, p < 0.01) and ferritin levels (median 649 [IQR 492–1,168] ng/dl vs. 393 [IQR 156–1,440] ng/dl, p = 0.02) than normonatremic patients. Hyponatremia was associated with higher odds of an abnormal hsCRP (unadjusted OR 5.03, 95%CI: 2.52–10.03), and remained significant after adjustment for potential confounders (adjusted OR 4.70 [95%CI: 2.33–9.49], p < 0.01). Hyponatremic patients had increased mortality on unadjusted (HR 3.05, 95%CI: 2.14–4.34) and adjusted (HR 2.76, 95%CI:1.88–4.06) in Cox proportional hazard models. Crude 30-day survival was lower for patients with hyponatremia at admission (mean [SD] survival 22.1 [0.70] days) compared with patients who were normonatremic (mean [SD] survival 27.2 [0.40] days, p < 0.01).Conclusion: Mild hyponatremia on admission is common, is associated with systemic inflammation and is an independent risk factor for hospital mortality.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT04493268.