Immunotherapy with immune checkpoint inhibitors represents nowadays a marked improvement in cancer treatment. Nevertheless, they can cause severe toxicities that put the patient at high risk, often requiring aggressive treatment. We present the case of a female patient who developed a severe immune-related adverse reaction to Pembrolizumab prescribed for melanoma treatment. Her array of symptoms, which presented a few days after last drug administration, consisted of severe neurological deficit, severe renal failure, polymyositis, and hyperthyroidism. Treatment required the immediate interruption of the trigger drug, infusion of high dose steroids, renal replacement therapy, plasmapheresis, and methimazole, as will be further discussed.