Acute graft-versus-host disease (GVHD) is a rare complication of pancreas transplantation. We describe a 54-year-old male with type 1 diabetes who received a zero-antigen mismatched pancreas-after-kidney transplant from a pancreas donor who was homozygous at the HLA-B, -Cw, -DR, and -DQ alleles. Starting on postoperative day (POD) #22, the patient developed persistent fevers. Workup was notable only for low-grade cytomegalovirus viremia, which was treated. The fevers eventually disappeared. On POD #106, the patient was noted to have a diffuse erythematous rash. A skin biopsy was consistent with GVHD. Short tandem repeat DNA analysis of both peripheral blood lymphocytes and skin demonstrated mixed chimerism, confirming the diagnosis of GHVD. Soon after diagnosis, the patient developed pancytopenia and fevers and died of multiorgan failure on POD #145. Transplant clinicians should consider GVHD as a possible, although admittedly rare, cause of fevers of unknown origin in recipients of pancreas transplants.