Abstract Background Immunosuppression is generally suggested in patients with specific subtypes of acute myocarditis, such as eosinophilic myocarditis or giant cell myocarditis or associated with systemic autoimmune disorders. In contrast, no specific treatment for most acute myocarditis complicated by acute heart failure (HF) or cardiogenic shock is recommended beyond the management of acute HF and supportive therapy. Nevertheless, large registries commonly reported using corticosteroids in severe forms without data supporting this strategy. Purpose To assess the safety and efficacy of high-dose pulse intravenous (IV) corticosteroid therapy to treat patients with complicated/fulminant acute myocarditis based on clinical suspicion. Methods An international pragmatic investigator-initiated single-blinded randomized controlled trial that screens patients between 18 and 70 years admitted to the hospital for suspected acute myocarditis (cardiac symptoms onset within three weeks) complicated by acute HF/cardiogenic shock and left ventricular (LV) ejection fraction<41% without significant LV dilation is ongoing. Patients are randomized in a 1:1 ratio to pulsed IV methylprednisolone (1 g) in saline solution (250 mL) daily for three days or placebo (saline without methylprednisolone) on top of standard therapy and maximal supportive care. A final diagnosis of myocarditis is confirmed by histology or cardiac magnetic resonance imaging. A population of 288 patients has been planned to assess a reduction in the probability of reaching the primary endpoint from 25% in the placebo arm to 12% in the methylprednisolone arm with a power of 0.80 (Figure). The main analysis will be conducted on an intention-to-treat basis. Results The primary efficacy endpoint of the trial is defined as the time from randomization to the first event occurring within 6 months, including all-cause death, heart transplantation, or long-term LV assist device implant, or need for an upgrading of the temporary mechanical circulatory support (t-MCS), or ventricular tachycardia (VT)/fibrillation (VF) treated with direct current (DC) shock, or first rehospitalization due to HF or VT/VF, or advanced atrioventricular block. The safety endpoints include a composite of potential complications that can occur, including serious infections, acute gastrointestinal bleeding, and other complications that can be related to corticosteroid therapy or prolonged stay on t-MCS. There are 32 active centers, and 48 patients have been randomized since December 2021. The trial is expected to be completed by the end of 2028. Conclusion The results of the MYTHS trial can define the role of IV methylprednisolone in the initial treatment of patients with complicated forms of acute myocarditis that currently have an unacceptably high mortality rate.