Background: The optimal use of the metabolic tumor response measured by ¹⁸fluorodeoxyglucose positron emission tomography (FDG-PET) in the treatment of esophageal cancer is currently unknown. We launched a phase II clinical trial to evaluate the early metabolic response to one-cycle chemotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) patients, who subsequently received neoadjuvant chemoradiation (neo-CRT) followed by surgery. Methods: ESCC patients with stage T3 or N1M0 or M1a (AJCC, 6th edition) were enrolled to receive one-cycle chemotherapy, day 1 and 8 doses of paclitaxel, cisplatin, and 24-hour infusional 5-fluorouracil and leucovorin, followed by paclitaxel/cisplatin- based 40Gy neo-CRT and surgery. FDG-PET was performed at baseline and day 14 of the one-cycle chemotherapy. The primary endpoint is pathological complete response (pCR) to neo-CRT. We hypothesized that early PET responders, defined as > 35% reduction of maximum standardized uptake value (SUV_max) from the baseline, would significantly improve pCR. Results: Between Feb 2008 and Mar 2012, 66 patients (M: F = 61: 5) were enrolled. Their clinical stages were: II or III, 56; IVA, 10. Forty seven received surgery. The pCR rate per surgical population was 34.0%. The median progression-free survival (PFS) and overall survival (OS) for the whole study group was 16 months (95% CI 9-27) and 22 months (95% CI 16-40), respectively. A total of53 patients were evaluable for PET response. The early PET response was not associated with high pCR rate or better survivals. However, in an exploratory analysis, the post-chemotherapy SUV_max was an independent prognostic factor for pCR, PFS and OS. A predictive model for pCR composed of weight loss and the post-chemotherapy SUV_maxwas established with an AUC of 0.84. Conclusions: Our study failed to validate the predictive value of predefined early PET response to one-cycle chemotherapy for pCR to neo-CRT in locally advanced ESCC patients. However, the FDG-PET SUV_max after one-cycle chemotherapy may have prognostic and predictive significance, and may be explored in further studies. Clinical trial information: NCT01034332