Preoperative chemoradiation therapy (CRT) in patients with locally advanced rectal cancer allows for radical surgery with sphincter preservation in many patients. To determine whether patients downsized with preoperative CRT may be potential candidates for local excision, we investigated residual disease patterns after neoadjuvant treatment. A retrospective analysis was carried out of patients with T3 or T4 rectal adenocarcinoma who were treated with neoadjuvant CRT. Clinical and pathologic data were analyzed to (1). determine the response rates to preoperative CRT in the tumor bed and regional nodal basin and (2). identify the incidence of residual disease in the mesorectum in patients downsized to <or=T2. A total of 219 patients met the inclusion criteria. Preoperatively 193 patients (88%) were staged as T3, and 99 patients (47%) had clinical N1 disease. The pathologic complete response rate was 20% (43 of 219 patients). T stage was downsized in 64% of the patients (140 of 219), and 69% (67 of 97) of the patients with clinical N1 disease were rendered node negative. Seventeen percent (21 of 122) of patients downsized to <or=T2 had residual disease in the mesentery. With a median follow-up of 40 months, 182 patients (83%) remain alive and free of disease. Nine patients (4.1%) have had a local recurrence. Although tumor response rates to preoperative CRT within the bowel wall and lymph node basin are similar, one in six patients with pT0-2 tumors will have residual disease in the rectal mesentery and nodes. Despite a substantial reduction in tumor volume with neoadjuvant CRT, local excision should be recommended with caution in patients with locally advanced rectal cancer.