A previously reported Phase I/II multimodality program for non-resectable hepatocellular cancer began with external beam-radiation and chemotherapy, followed by administration of 131I antiferritin-specific radioimmunoglobulin and led to a 48% remission (7% complete remission and 41% partial remission). Survival and response depended on alpha fetoprotein status. AFP+ patients had a median survival of 5 months; AFP- patients had a median survival of 10.5 months. No acute effects occurred relative to treatment with radiolabeled antibody. A randomized prospective study was designed to compare full dose chemotherapy consisting of 60 mg/m2, doxorubicin and 500 mg/m2 of 5-fluorouracil administered every 3 weeks, to 131I antiferritin administration every 8 weeks and allowed for crossover treatment if tumor progression occurred. Overall, radiolabeled antibody administration and full dose chemotherapy led to equivalent partial remission rates (22-30% vs 23-25%) and survival rates compared to chemotherapy (6 month median; AFP+ 5 months; AFP- 10 months). The most important new observations were the response in AFP- patients who, following chemotherapy failure, achieved remission using 131I radiolabeled antibody (7/11) and a subset of patients (7%) who were treated with radiolabeled antibody and converted from non-resectable to resectable status followed by surgical excision.