BACKGROUND In the treatment of locally advanced rectal carcinoma, radiation therapy before surgery has been shown to decrease local recurrence rates, but has minimal effect on survival. Recently, chemotherapy in combination with preoperative radiation therapy has been shown to be effective for certain malignancies. We postulated that such combination therapy might improve the resectability of advanced rectal cancer. METHODS During a 4-year period we treated 20 patients with locally advanced adenocarcinoma of the rectum using a protocol of preoperative simultaneous pelvic irradiation (4,030-6,040 cGy) and infusion chemotherapy (5-fluorouracil 100 mg/m2 per day over 96 hours and mitomycin 10 mg/m2) followed by surgical resection. Effects of therapy on resectability, tumor size, recurrence and survival, and complications of treatment were evaluated. RESULTS Minimal toxicity was observed and all patients completed their scheduled preoperative therapy. Reduction in tumor size after chemoradiation, as measured by CT scan, averaged 61% (range 20-100%). Twenty percent had a complete pathologic response to preoperative therapy, with no tumor found in the surgical specimen. Using Kaplan-Meier survival curves, the 5-year survival was estimated to be 64+/-11%, and cancer free and local pelvic control rates were 41+/-12% and 88+/-8% respectively. CONCLUSIONS We believe that preoperative combination radiation and chemotherapy may provide significant benefit for patients with locally advanced rectal cancer, and that further, large scale studies of this treatment regimen are warranted.