Background: A multicenter, single-arm, confirmatory trial (CRES³T) was conducted to investigate the efficacy and safety of S-1 plus cisplatin and concurrent radical-dose thoracic radiotherapy (TRT) followed by surgery in patients with superior sulcus tumor (SST). To date, no clinical trials on radical-dose TRT in the induction setting for SST have been conducted. Methods: SST was defined as a tumor that directly invades the chest wall including the first rib or more cephalad, subclavian artery, or subclavian vein according to CT or MRI scans. Eligible patients were 20 to 75 years old and had pathologically proven non-small cell lung cancer, performance status of 0–1, and no history of prior treatment. The patients received induction therapy consisting of three cycles of S-1 plus cisplatin with concurrent TRT (66 Gy in 33 fractions) followed by surgery. S-1 was administered orally at 40 mg/m² twice per day, on days 1–14 along with an intravenous infusion of cisplatin (60 mg/m²) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was the 3-year overall survival (OS) rate, and key secondary endpoints included progression-free survival (PFS) rate, objective response rate (ORR), pathological complete remission (pCR) rate, and toxicity. Results: Between June 2014 and March 2019, 61 patients registered and received induction therapy. Pathological diagnoses were 30 adenocarcinoma, 20 squamous cell carcinoma, and 11 others. Radiologically diagnosed tumor invasion sites were the chest wall (n=57), subclavian artery (n=18), and subclavian vein (n=10). One patient with distant metastasis that manifested after starting induction therapy was removed from this study. Forty-nine patients underwent lobectomy and resection of the involved sites. The complete resection rate was 98% (48/49). Median follow-up time was 54 months. The 3-year OS and PFS rates were 73% (95% CI: 60–83%) and 53% (95% CI: 40–65%), respectively. The ORR and pCR rate were 42% (25/60, 95% CI: 29–54%) and 33% (16/49, 95% CI: 20–46%), respectively. Grade (G) 3 or 4 toxicities during induction therapy included neutropenia (28%), anemia (13%), thrombocytopenia (5%), and hyponatremia (8%). Two (3%) cases of pneumonia resulted in death. G3 surgical complications such as supraventricular arrhythmia, chylothorax, pleural effusion, pneumonia, mediastinitis, wound infection, and arm neuropathy developed in one (2%) patient each. One (2%) cardiac arrest on postoperative day 3 resulted in death. Conclusions: CRES³T demonstrated that induction therapy using S-1 plus cisplatin and concurrent radical-dose TRT followed by surgery was safe and effective in treating SST. Therefore, this strategy is potentially a new standard treatment for SST. (UMIN: 000014386, jRCT: s031180401.). Clinical trial information: UMIN000014386.