PURPOSE: Although F-18 fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) holds great potential for determining tumor response to neoadjuvant therapy, its efficacy in primary rectal cancer is not well-established. The goal of this study was to determine the ability of serial FDG-PET/CT to predict tumor down-staging and the percentage of residual tumor in resected specimens of primary rectal cancer. METHODS: Primary rectal cancer patients undergoing neoadjuvant therapy and definitive surgical resection at a single institution were included. All tumors were ≤12cm from the anal verge and assessed for size and stage with endoscopic ultrasound (EUS) (n = 16) or MRI (n = 1). FDG-PET/CT was obtained prior to and 4 weeks following completion of neoadjuvant therapy. FDG-PET/CT parameters used to determine tumor response included visual response score (VRS), standardized uptake value (SUV), PET-derived tumor volume (PETvol), CT-derived tumor volume (CTvol), and total lesion glyocolysis (δTLG). Primary outcome measures included percentage residual tumor using pathological response score (PRS) (0: no response/progression, 1: <33%, 2: 34-66%, 3: 67-95%, 4: 96-10%), tumor down-staging, and lymph node status based upon pretreatment staging and final pathology. RESULTS: From May 2003 to October 2005, 17 patients with primary rectal cancer (10 male, median age 63) underwent neoadjuvant treatment (2 CT, 2 RT, 13 CT/RT) and serial FDG-PET/CT. Preoperative staging demonstrated uT2N1 (3, 18%), uT3N0 (3, 18%), uT3N1 (7, 41%), cT3N2 (1, 6%), uT4N1 (2, 12%), and uT4N2 (1, 6%). All parameters studied on serial FDG-PET/CT were significantly greater (p<0.001) in patients demonstrating a pathological response to treatment (n = 14). The percentage of residual tumor in resected specimens (PRS 0 - 4) correlated best with VRS (r=0.60, p=0.011) and ΔCTvol (r=0.59, p=0.012). VRS (p=0.044) and ΔSUV (p=0.029) were able to predict patients with tumor down-staging (n = 11). Although FDG-PET/CT was unable to predict the presence of positive lymph nodes on EUS, the presence of positive lymph node disease on final pathology (n = 5) was associated with lower VRS (p=0.018), ΔCTvol (p=0.045), and ΔPETvol (p=0.043). CONCLUSION: Serial FDG-PET/CT parameters are effective for predicting tumor down-staging, the percentage of residual tumor, and final lymph node status following preoperative treatment of primary rectal cancer. Accurate assessment of tumor response to neoadjuvant therapy can assist in surgical treatment planning for rectal cancer.