Purpose: Patients with locally advanced rectal carcinoma are at risk for both local recurrence and distant metastases. We demonstrated the efficacy of preoperative hyperfractionated accelerated radiotherapy (HART). In this Phase I trial, we aimed at introducing chemotherapy early in the treatment course with both intrinsic antitumor activity and a radiosensitizer effect. Methods and Materials: Twenty-eight patients (19 males; median age 63, range 28–75) with advanced rectal carcinoma (cT3: 24; cT4: 4; cN : 12; M1: 5) were enrolled, including 8 patients treated at the maximally tolerated dose. Escalating doses of CPT-11 (30–105 mg/m2/week) were given on Days 1, 8, and 15, and concomitant HART (41.6 Gy, 1.6 Gy bid 13 days) started on Day 8. Surgery was to be performed within 1 week after the end of radiochemotherapy. Results: Twenty-six patients completed all preoperative radiochemotherapy as scheduled; all patients underwent surgery. Dose-limiting toxicity was diarrhea Grade 3 occurring at dose level 6 (105 mg/m2). Hematotoxicity was mild, with only 1 patient experiencing Grade 3 neutropenia. Postoperative complications (30 days) occurred in 7 patients, with an anastomotic leak rate of 22%. Conclusions: The recommended Phase II dose of CPT-11 in this setting is 90 mg/m2/week. Further Phase II exploration at this dose is warranted. © 2003 Elsevier Inc.