Primary hepatocellular carcinoma is one of the most common malignancies worldwide. Isolated hepatic perfusion (IHP) is a regional treatment technique that isolates the organ to allow delivery of high-dose chemotherapy, biological agents, and hyperthermia directly to unresectable cancers confined to the liver. This study presents our experience using IHP with melphalan with or without tumor necrosis factor (TNF) to treat patients with hepatocellular carcinoma or adenocarcinoma of hepatobiliary origin. Nine patients with unresectable primary hepatic malignancies underwent a 60-minute IHP with 1.5 mg/kg melphalan with or without 1.0 mg TNF. Four patients failed one or more previous treatment regimens, and the mean hepatic replacement by tumor was 41% (range 10% to 75%). Patients were monitored for response, toxicity, time to recurrence, and survival. Six (67%) of nine patients experienced greater than 50% regression of tumor by objective radiographic imaging and an additional patient had a 45% reduction in tumor burden. Mean time to progression was 7.7 months for those who responded to treatment. Patients who had a response to therapy had an average overall survival of 16.3 months. IHP can be performed safely and has significant antitumor activity in patients with unresectable primary hepatic malignancies. Hepatic progression continues to be the dominant factor influencing survival in this group of patients.