A 72-year-old female was admitted with severe calciphylaxis-associated bilateral leg pain on a background of end-stage renal failure on hemodialysis. Palliative care input was requested, and following transfer to our unit she was commenced on low-dose methadone as adjunctive analgesic therapy. A remarkable and sustained analgesic response was observed. Calciphylaxis is associated with severe pain, and careful consideration of analgesic agents and their pharmacokinetics in patients with end-stage renal failure is required.