A surgically unresectable, biopsy-proven hepatocellular carcinoma (HCC) developed in a 63-year-old man with cirrhosis. He survived 24 months without treatment. During that time the tumor burden decreased as demonstrated both radiologically and by the normalization of alpha-fetoprotein levels. The patient died of complications secondary to repeated esophageal variceal hemorrhage. Necropsy demonstrated prominent, ulcerated esophageal varices and liver cirrhosis without evidence of neoplasia either grossly or on a subsequent thorough microscopic examination. This case represents the first confirmation of HCC spontaneous regression in which a primary histologic diagnosis was confirmed by immunohistochemical and flow cytometric DNA analysis, and where tumor regression was proven by a thorough necropsy examination.