OBJECTIVE: The aims of this analysis were to determine prospectively the effects of surgical resection and radiation therapy on the length and quality of survival as well as late toxicity in patients with perihilar cholangiocarcinoma. BACKGROUND: Retrospective analyses have suggested that adjuvant radiation therapy improves survival in patients with perihilar cholangiocarcinoma. However, in these reports, patients receiving radiotherapy tended to have smaller, often resectable tumors, and were relatively fit. In comparison, patients who have not received radiotherapy often had unresectable tumors, metastatic disease, or poor performance status. METHODS: From 1988 through 1993, surgically staged patients with perihilar cholangiocarcinoma and 1) no evidence of metastatic disease, 2) Karnofsky score > 60, 3) no prior malignancy or radiotherapy, and 4) a patent main portal vein were analyzed. Fifty patients were stratified by resection (n = 31) versus operative palliation (n = 19) and by radiation (n = 23) versus no radiotherapy (n = 27). RESULTS: Patients undergoing resection had smaller tumors (1.9 +/- 2.8 vs. 2.4 +/- 2.1 cm, p < 0.01) that were less likely to invade the hepatic artery (3% vs. 42%, p < 0.05) or portal vein (6% vs. 53%, p < 0.05). Multiple parameters that might have affected outcome were similar between patients who did and did not receive radiation therapy. Resection improved the length (24.2 +/- 2.5 vs. 11.3 +/- 1.0 months, p < 0.05) and quality of survival. Radiation had no effect on the length (18.4 +/- 2.9 vs. 20.1 +/- 2.4 months) or quality of survival or on late toxicity. CONCLUSIONS: This analysis suggests that in patients with localized perihilar cholangiocarcinoma, resection prolongs survival whereas radiation has no effect on either survival or late toxicity. Thus, new agents or strategies to deliver adjuvant therapy are needed to improve survival in these patients.