INTRODUCTION: Calciphylaxis, also known as calcific uremic arteriolopathy (CUA), is a rare and potentially fatal condition primarily affecting patients with end-stage renal disease (ESRD) on hemodialysis (HD). It is characterized by calcification in small blood vessels, leading to painful skin ulcers and high mortality rates. CASE DESCRIPTION: This is a case of a 42-year-old female with ESRD on HD who developed calciphylaxis, presenting with non-healing ulcers on her thighs. DISCUSSION: Despite initial treatments, including wound care and pain management, her condition did not improve. A skin biopsy was inconclusive, highlighting the diagnostic challenges associated with calciphylaxis. Based on clinical judgment, warfarin and calcium-based therapies were discontinued, and the patient's HD regimen was adjusted. Due to the persistence of symptoms, sodium thiosulfate (STS) therapy was initiated, leading to significant improvement in her ulcers after six months of treatment. CONCLUSIONS: This case highlights the importance of clinical judgment in the diagnosis and management of calciphylaxis, particularly when histopathological diagnostic methods yield inconclusive results. Clinical criteria, alongside a thorough assessment of the patient's history and presentation, are vital for achieving a timely diagnosis in such challenging cases. The successful use of sodium thiosulfate in this patient adds to the growing body of evidence supporting its use as a potential treatment for calciphylaxis, especially in cases that do not respond to conventional therapy.