We present four cases of proximal calciphylaxis in end-stage renal disease patients treated with hemodialysis. All patients were diabetic and developed lesions in areas that had previously served as sites of insulin injection. We review the presentation, pathogenesis, pathology, prognosis, and treatment of this devastating condition. Finally, we hypothesize that subcutaneous injection of insulin may play a pathogenic role in the development of proximal calciphylaxis.