BACKGROUND This case report is the first documentation of the occurrence and potential source of lethal graft-versus-host disease (GVHD) after simultaneous kidney-pancreas transplantation. The patient was a 27-year-old African-American male who received an ABO-compatible, five HLA antigen-mismatched kidney-pancreas transplant from a 17-year-old African-American female donor, who died after childbirth. METHODS Preoperative crossmatches using lymphocytotoxicity and flow cytometry were negative. The patient received four blood transfusions within 10 days of transplantation. Immunosuppression consisted of OKT3 induction, and then cyclosporine, azathioprine, and corticosteroids. RESULTS On postoperative day (POD) 9, the patient became febrile, and leukocytopenia and pancytopenia developed. Immunosuppression was reduced and granulocyte colony-stimulating factor was begun. Cultures were negative, interleukin 6 and interleukin 8 levels were elevated, and a cutaneous rash appeared on POD 18. A skin biopsy demonstrated dermatitis with focal epidermal necrosis consistent with GVHD. In an attempt to identify the source of GVHD, variable-number tandem repeat analysis fingerprinting was performed with DNA from donor splenocytes, from the skin biopsy, as well as from the patient's buccal mucosa. The skin biopsy showed a mixed variable-number tandem repeat analysis type containing DNA fragments matching the recipient and donor. Blood donors were excluded as a source because they were serologically different from the organ donor. The patient developed liver abnormalities and died from multiorgan failure on POD 22. CONCLUSIONS We speculate that carryover of passenger donor lymphocytes within the transplanted organ were responsible for GVHD. Furthermore, donor traits such as sexual mismatching, African-American race, and alloimmune status may be important potential risk factors for GVHD.