Introduction <p>Immune checkpoint inhibitors (ICIs) have been used for various malignancies over the last two decades. Although very efficacious, they are associated with a broad spectrum of severe and potentially life-threatening adverse events. There are rare instances where ICIs can cause myositis, myocarditis, and myasthenia gravis overlap syndrome. This is a fatal case of ICI-associated myocarditis, myositis, and myasthenia gravis overlap syndrome (IM3OS) in a patient with an undiagnosed thymoma, underscoring the need for vigilance in this high-risk group.</p> <p>Case Presentation.</p> <p>We present the case of a 70-year-old man with thymoma who developed severe orthopnea and exertional dyspnea 2&#xa0;weeks after the first dose of pembrolizumab for adjuvant treatment of right toe malignant melanoma. He was tachypneic with normal oxygen saturation in the room air. He had deranged liver function tests and a new right bundle branch block. He developed ST elevations in lateral chest leads along with significant troponin elevation. His cardiac catheterization showed no significant coronary artery disease. Given the clinical suspicion of immune-mediated myocarditis, he was treated with methylprednisolone. However, due to worsening of diplopia and lack of respiratory status improvement, creatinine kinase was obtained, which was elevated, leading to suspicion of myasthenia gravis and myositis. The patient was treated with intravenous immunoglobulins and high-dose steroids. However, despite aggressive treatment and transfer to a tertiary care center, the patient had fatal respiratory failure.</p> Conclusion <p>The diagnosis of ICI-associated IM3OS can be challenging, and limited data is available to guide treatment.</p>