BACKGROUND Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced malignancies but can cause life-threatening immune-related adverse events. Myocarditis, myositis, and myasthenia gravis (MMM) overlap syndrome is a rare, highly morbid complication with high mortality. Most cases develop early in therapy, sometimes after a single dose. CASE REPORT A 73-year-old man with resected stage IIIC malignant melanoma presented 4 weeks after his first dose of adjuvant nivolumab with progressive weakness, gait instability, dyspnea, and dark-colored urine. Workup revealed markedly elevated troponin (11 162 ng/L), creatine kinase (5518 IU/L), and transaminases (aspartate transaminase 614 IU/L, alanine transaminase 497 IU/L), with new right bundle branch block on electrocardiography. ICI-associated myocarditis, myositis, and hepatitis were diagnosed; high-dose intravenous methylprednisolone was initiated. He subsequently developed diplopia, ptosis, bulbar weakness, and respiratory compromise from myasthenia gravis, prompting plasmapheresis and pyridostigmine. He improved with escalating immunosuppression and was discharged on oral prednisone and pyridostigmine after 16 days. Nivolumab was permanently discontinued. Two and a half weeks later, he had a fatal out-of-hospital cardiac arrest. CONCLUSIONS This case illustrates the severe and unpredictable course of MMM overlap syndrome after a single dose of nivolumab. Despite early aggressive immunosuppression and apparent recovery, the patient had a delayed fatal cardiac event. Given the risk of relapse during corticosteroid taper, structured post-discharge cardiac surveillance with serial troponin and ambulatory rhythm monitoring may help detect subclinical activity or arrhythmia. Prospective studies are needed to define optimal monitoring and identify predictors of late mortality.