Introduction. Coronavirus disease 2019 (COVID-19) is the systemic entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may cause death through severe atypical pneumonia and acute lung injury. Valproic acid (VPA) has shown anti-inflammatory activity and intrinsic antiviral effect. These properties warrant the study of VPA as a possible active treatment in people with severe COVID-19. Material and Methods. Consecutive adult patients needing invasive mechanical ventilation (IMV) will be given intravenous (IV) VPA at a starting dose of 20 mg/kg/day and up to 60/kg/day (in 60 min IV infusions in 250 mL normal saline) as needed to reach plasma VPA concentrations of 50-100 μg/mL (measured every 72 h). These patients will be followed-up for 10 days for the primary outcome and for a further period of 30 days after treatment completion for the secondary outcome of recurrence. The primary study outcome is the reduction in the case fatality rate (CFR) of at least 50 % after 10 days of treatment (as compared with natural history). Secondary outcomes are the reduction of length of stay (LOS) of at least 50 %, as well as COVID-19 recurrence at 30-day follow-up. The most important safety outcomes are acute liver failure, acute pancreatitis, and thrombocytopenia. Conclusions. Although long-term adverse effects and even pro-inflammatory consequences have been reported with the chronic use of VPA, the study of VPA is justified from a scientific standpoint given the urgent need for a drug against COVID-19 to shorten the high mortality and LOS.