Background: For clinical(c) stage I submucosal (T1b) thoracic ESCC, surgery with lymph node dissection is the standard treatment. However, pathologic diagnosis after resection sometimes reveals mucosal cancer (T1a), which is treatable by endoscopic resection (ER) alone. T1b ESCC is also treatable with chemoradiotherapy (CRT) but has risk of loco-regional failure and cardiopulmonary adverse events (AEs). We investigated the efficacy and safety of combined ER+CRT for cT1b ESCC. Methods: The eligibility criteria included: histologically proven thoracic ESCC, T1b diagnosed by endoscopic ultrasound, cN0M0, primary tumor size ≤ 5 cm and esophageal lumen circularity ≤ 3/4, and age 20-75 years. After ER, additional treatment was indicated by histologic diagnosis: Group A, pT1a with negative resection margin and no vascular invasion -no additional treatment; Group B, pT1b with negative resection margin and pT1a with vascular invasion -prophylactic CRT; Group C, pT1b with positive resection margin -definitive CRT. Chemotherapy comprised of 5-fluorouracil (700 mg/ m²/day, days 1-4 and 29-32, civ), and cisplatin (70 mg/ m²/day, days 1 and 29). Radiotherapy dose was 41.4 Gy/23 fr, delivered to the loco-regional lymph-node area (Group B) or 50.4 Gy/28 frs with a boost to the primary site (Group C). Primary endpoint was 3-year overall survival (OS) of Group B. Key secondary endpoint was 3-year OS of all enrolled patients (pts). The required sample size was 82 for primary analysis, with one-sided alpha of 0.05 and power of 90%, based on the expected and threshold 3-year OS as 90% and 80%. Results: Of 177 pts registered in 2006-2012 [M/F, 147/30; Age, 63 years (42-75); lesion diameter, 2.5cm (0.5-5.0)], ER was performed in 176 pts (Group A/B/C, 74/87/15). There were no grade 3/4 AEs due to ER; 8 of 96 pts who received CRT suffered from late cardio-pulmonary AEs. The 3-year OS was 90.7% (90% CI; 84.0-94.7) of 87 pts in Group B and 92.6% (90% CI; 88.5-95.2) overall. Conclusions: Combined ER+CRT for T1b ESCC is considered to be comparable to surgery in efficacy and can be new minimally invasive treatment option. Clinical trial information: 000000553.