Background: Coronavirus disease MESHD 2019 (COVID-19) is the systemic entity caused by the severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) that may cause death MESHD through severe atypical pneumonia MESHD pneumonia HP and acute lung injury MESHD. Valproic acid (VPA) has shown anti-inflammatory activity and mild intrinsic antiviral effect. These properties warrant the study of VPA as a possible active treatment in persons with severe COVID-19. Methods: Consecutive adult TRANS patients needing invasive mechanical ventilation (IMV) will be given intravenous (i.v.) VPA at a starting dose of 20 mg/kg/day and up to 60/kg/day (in 60 min i.v. infusions in 250 mL normal saline) as needed to reach plasma SERO VPA concentrations of 50-100 mcg/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 MESHD. The primary study outcome is the reduction in the case fatality rate 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 MESHD at 30-day follow-up. The most important safety outcomes are acute liver failure MESHD, acute pancreatitis HP pancreatitis MESHD, and thrombocytopenia MESHD thrombocytopenia HP. Conclusion: Although long-term adverse effects MESHD and even pro-inflammatory consequences have been reported with the chronic use of VPA, given the urgent need for a drug against COVID-19 to shorten the high mortality and LOS, the study of VPA is justified from a scientific standpoint.