The occurrence of hepatocellular carcinoma (HCC) in renal transplant recipients has typically been associated with hepatitis B or C infection. We encountered two cases of HCC in renal transplant recipients with negative hepatitis B and C markers and no underlying liver pathology, in whom immunosuppression therapy consisted of prednisone and azathioprine (AZA). Patient no. 1 is a 66-year-old man with diabetes who underwent cadaveric renal transplantation 13 years before presentation. An ultrasound obtained for evaluation of a prolonged prothrombin time and decreased serum albumin level showed a suspicious nodular lesion in the left lobe of the liver. A computed tomographic (CT) scan confirmed a 4- × 5- × 5-cm mass that, on biopsy, was determined to be well-differentiated HCC. There was no evidence of metastasis, and the results of random biopsies of the surrounding parenchyma were normal. The patient underwent a left lateral segmentectomy, did well, and an initial alpha-fetoprotein (AFP) level of 85995 ng/mL decreased to 9 ng/mL. Approximately 20 months postoperatively, however, a surveillance CT scan showed three hypervascular lesions in the right lobe of the liver and the AFP level increased to 28,370 ng/mL. Subsequent percutaneous alcohol injections yielded good results, and the patient is alive and well 13 months later. Patient no. 2 is a 57-year-old man who underwent cadaveric renal transplantation 24 years earlier. A CT scan of the abdomen obtained for evaluation of lower abdominal pain showed a 4- × 4- × 6.5-cm mass in the right lobe of the liver that, on biopsy, was found to be poorly differentiated HCC. Multiple biopsies of adjacent liver parenchyma showed no evidence of cirrhosis, AFP level was normal, and imaging studies showed no evidence of tumor spread. The patient underwent a right hepatic lobectomy and is doing well without evidence of recurrence 27 months postoperatively. Our two patients had no evidence of viral hepatitis, cirrhosis, or metabolic liver disease, yet both developed HCC. The use of AZA may have had a role in the development of HCC. In renal transplant recipients on long-term immunosuppression therapy, particularly AZA, it is prudent to maintain a high index of suspicion for HCC when liver enzyme level or function abnormalities are encountered.