3552 Background: Local recurrence after surgery is a cause of treatment failure in pts with locally advanced rectal cancer (LARC). Preoperative RT decreases local recurrence but not distant spread. Oxaliplatin (OX) and capecitabine (CAP) are both highly active cancer drugs for advanced colorectal cancer and have radiosensitizing properties. Therefore, adding CAP and OX to preoperative RT should improve its efficacy in terms of local control and prevention of metastases. Methods: This study was designed to investigate the efficacy (based on pathological response rate) and safety of preoperative chemo-RT in patients with LACR (T3-T4 and/or N+ staged by endorectal ultrasound). RT was administered for 5 weeks, 5 days a week (1.8 Gy/fraction, total dose 45 Gy, 3D conformation technique) in combination with OX 50 mg/m2 intravenously, weekly for 5 weeks and oral CAP 825 mg/m2 twice a day, each day of radiation. Surgery was performed 6–8 weeks after completion of RT. Results: Since December 2002, 37 out of the 40 planned pts were enrolled. 31 pts (ECOG 0–2; median age 60 y, ranging from 33 to 82; males/females 16/15) are evaluable for toxicity and 17 for pathological response after surgery. Neurotoxicity was very limited, as only 10 pts (32%) experienced mild (grade I) neurotoxicity. The most frequent grade 3–4 NCI CTC toxicity was diarrhea: 7/31 pts (22%). 1 of these pts died of candida septicemia 6 wks after the last chemotherapy infusion. Total OX and CAP dose received was 92% and 93 % of the planned dose, respectively. The main reason to reduce chemotherapy dosages was diarrhea occuring at 4–5th week of the treatment. RT had to be interrupted in 2 pts due to diarrhea (total dose received 27 and 39.6 Gy). To date, 17 resected rectal specimens were reviewed by the same pathologist. 1/17 had a pathological complete remission and 5 had only microfoci of residual tumor. Conclusions: These results demonstrate that preoperative OX and CAP in combination with RT is feasible in pts with LARC. As expected, the only clinically relevant toxicity was diarrhea. Dose intensity of chemotherapy and RT was high. Updated data will be presented at the meeting. No significant financial relationships to disclose.