Forty-nine patients with locally advanced carcinoma of the pancreas were treated in a randomized, prospective study comparing definitive helium ion radiation therapy with conventional split-course megavoltage photon irradiation. Patients in each treatment arm underwent exploratory staging laparotomy followed by concurrent radiation therapy and 5-fluorouracil chemotherapy. Patients treated with photons received 6,000 cGy over a period of 10 weeks; patients treated with helium irradiation received a 6,000-7,000-cGy-equivalent dose over a period of 8-9 weeks. There was no significant difference in overall survival between patients in the two treatment arms (P = .29). Patients treated with helium ions had a slightly longer median survival (7.8 months) than the photon-treated patients (6.5 months). Local control rates were slightly higher in the helium-treated patients (10% vs 5%). Complications included one chemotherapy-related death. Four of the five helium-treated patients who survived longer than 18 months died of local failure without distant metastases. These results suggest that more aggressive local therapy could result in improved survival in helium-treated patients.