This phase II trial was undertaken to determine the efficacy and toxicity of proton beam radiotherapy for patients with locally unresectable hepatocellular carcinoma. Cirrhotic patients were eligible if they had a Child-Pugh score of 10 or less. Eligible patients included those with T 1 -T 3 hepatocellular carcinoma; selected T 4 patients also were eligible. Patients with lymph node or distant metastases were ineligible. Daily proton beam radiotherapy was directed to the liver tumor with an additional 1-2 cm margin. The total dose was 63 cobalt Gray equivalents, administered in 15 divided fractions over 3 weeks. Thirty-four patients have completed treatment and have been followed up for a minimum of 6 months, with a median follow-up period of 20 months. The mean age was 65 years, and average tumor size was 5.7 cm. Posttreatment toxicity included a small but significant decline in albumin levels and increased total bilirubin; 3 experienced duodenal or colonic bleeding when bowel was immediately adjacent to the treated tumor. Two-year actuarial data showed a 75% local tumor control rate and an overall survival rate of 55%. Of patients with an elevated pretreatment alpha-fetoprotein, 85% were found to have declining alpha-fetoprotein levels from a pretreatment mean of 1405 to 35 at 6 months after treatment. Six patients underwent liver transplantation between 6 and 16 months after completion of radiotherapy with 2 showing no evidence of residual carcinoma within the explanted liver. Overall the majority of patients responded to treatment, and the therapy was well tolerated.