Background: Current treatment results in locally advanced esophageal cancer (LAEC) are far from being satisfying. This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative CRT in this disease. Methods: Patients (pts) with potentially resectable LAEC (T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A) received an induction cycle of cisplatin 100 mg/m², day 1, and 5-FU 1000 mg/m²/day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy given concurrently with 2 cycles of cisplatin 75 mg/m² and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m², with a loading dose of 400 mg/m², starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: 64 pts were enrolled and 60 completed CRT. Median age was 65 years (range: 38-84 years) and 66% were males. The SqCC/adenocarcinoma ratio was 39%/61% (25/39). Pts had very advanced tumors: 95% T3-T4, 67% N1 and 19% M1A. The most common grade > 3 toxicities were leucopenia (45% of pts) and neutropenia (41%). There were two cases (3%) of fatal toxicities (neutropenic sepsis and sudden death). Among the 55 operated pts, R0 resection was achieved in 51 (93%). There were 8 cases (14.5%) of postoperative mortality, due to infection (3 pts), esophageal leak (2), bleeding (2) and pulmonary insufficiency (1). Pathological down-staging was noted in 72% of pts and pathological complete response (pCR) in 33%. 5y-local control, progression-free survival (PFS) and overall survival (OS) rates for all pts were 94%, 40%, 39%, respectively. Pts with SqCC had a significantly higher pCR rate (52% vs 15%, p = 0.007), 5y-PFS (67% vs. 21%, p = 0.008) and 5y-OS (64% vs. 20%, p = 0.019). Conclusions: This study suggests that the addition of cetuximab to standard preoperative CRT is safe. R0, pCR, local control and long term PFS and OS rates in pts with SqCC tumors are encouraging. Further evaluation of this approach in this population seems warranted.