We present a case of severe hyperammonemia with subsequent brain herniation in an adult man after renal transplantation. After successful surgery and an initially uneventful postoperative course, the patient developed significant mental status changes associated with seizure activity. His condition rapidly deteriorated, requiring mechanical ventilation and cardiovascular support. Laboratory studies at that time demonstrated an increased serum ammonia level without evidence of liver or kidney dysfunction. Further investigation revealed an increased orotic acid level in the urine, suggesting a urea cycle disorder (UCD). Despite aggressive therapy, the patient's condition continued to deteriorate. Magnetic resonance imaging demonstrated severe brain edema with no cerebral perfusion; after consultation with the family, care was withdrawn. The combination of hyperammonemia and elevated urine orotic acid with normal liver and kidney function suggested a UCD. It is important to note that patients with a UCD may be free of symptoms for many years. Several factors are able to trigger the disease in adulthood, leading to encephalopathy and death. In this case, the patient's seizures were initially assumed to be a side effect of immunosuppressive therapy. Further diagnostic measures were only performed late in the course of the disease, which delayed the diagnosis of UCD.