This study was undertaken to correlate change in fluorine-18 fluorodeoxyglucose positron emission tomography ((18)FDG-PET) uptake with response to combined-modality neoadjuvant therapy in patients with locally advanced rectal cancer. Twenty patients (13 male; 7 female) underwent (18)FDG-PET scans before and 3 to 4 weeks after completion of chemoradiation before surgery. Staging by endoscopic ultrasound was T3/T4 (17/1); two patients were unable to undergo endorectal ultrasound. Fifteen patients had perirectal lymphadenopathy. Median radiation dose was 5,040 cGy (range, 4,500 to 5,500 cGy). All patients received continuous infusion 5-fluorouracil (or capecitabine) with radiation. Median pre- and post-chemoradiation standard uptake values were 9.4 (range, 3.6 to 37.0) and 3.05 (range, 0.5 to 8.2), respectively. Median percent standard uptake value decrease observed in the postchemoradiation PET scans was 71% (range, 7% to 95%). Six patients (30%) had pathologic complete response. Only two of six patients with postchemoradiation standard uptake values <or=2.5 had a complete pathologic response. The time from the end of radiation to surgery was marginally significant for predicting pathologic complete response (P = .12). Neoadjuvant combined-modality therapy resulted in decreased metabolic activity on PET. Because response to preoperative treatment predicts clinical outcome, the utility of midtreatment PET scans to guide treatment decisions should be further explored in larger clinical studies.