The aim of this prospective study is to report our experience in the multimodal management of locally advanced esophageal squamous cell carcinoma (LAESC; stage III cTNM), focusing on the results of chemoradiotherapy followed by surgery. These findings were compared to the results of a standard group of patients with locally advanced esophageal carcinoma (LAEC; stage III pTNM) treated in our center with surgery alone. Sixty-one patients with LAESC underwent preoperative chemoradiotherapy (5-fluorouracil + cisplatin) with concomitant 45 Gray radiotherapy in a 5-week course. Transthoracic esophagectomy was performed 4 to 5 weeks after the end of the neoadjuvant therapy. Thirty-eight patients underwent surgery, and 37 of them had resections (resectability: 97% in the multimodal group; 84% in the standard surgical series; p = 0.07). The R0 (complete) resection rate was 78% compared to 56% in the standard surgical group (p <0.03). Eleven patients had no residual tumor in the resected specimen (pathologic complete response: pCR: 30%). The operative mortality rate was 19% compared with 8.8% in the standard series. The overall median survival of the resected patients was 21 months, with a 5-year survival rate of 11% (14% in the surgical group; NS). The 3-year and 5-year survival rates were 34% for the pCR group and respectively 5% and 0% for the group with pathologic incomplete response (pIR; p <0.05). The median survival was 28 months for the pCR patients and 19 months for the pIR group. In this non-randomized trial, preoperative chemoradiotherapy in LAESC seems to increase the resectability and R0 resection rates, to allow a higher pCR rate and a longer survival only in the pCR group, at the expense of an inadequate increase in operative mortality. This multimodal treatment cannot be proposed as a standard procedure unless less toxic regimens are developed, increasing the benefits with better local and distant failure control and decreasing operative mortality.