Background: To evaluate the efficacy and safety of chemoradiotherapy (CRT) concurrent with S-1 plus cisplatin in patients with unresectable locally advanced SCCHN. Methods: Eligibility criteria included histologically proven SCCHN with unresectable locally advanced lesions, PS 0-1, aged 20 to 75 years old, adequate organ function, and no prior treatment. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at 60 mg/m²/day, and cisplatin at 20 mg/m²/day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently startingon day 1. For patients achieving an objective response after CRT, two additional cycles of chemotherapy wereadministered. The primary endpoint was clinical complete response rate (%CR), which was the proportion of complete response (CR) and good partial response (good PR). Good PR was defined as remaining tissue with tumor shrinkage, which was not regarded as residual tumor but rather as scar material.The planned sample size was 45 patients, which was calculated by SWOG's two-stage attained design based on an expected %CR of 60% and a threshold of 45%, with a one-sided alpha of 0.1 and a power of 0.9. Results: From July 2008 to July 2010, 45 eligible subjects were accrued, including 43 males, with median age 63 years, ECOG PS 0/1 (36/9), oropharynx/ hypopharynx/larynx (26/15/4), T1/T2/T3/T4a/T4b (1/11/7/17/9) and N0/N2a/N2b/N2c/N3 (2/3/10/24/6). %CR was 64.4% (8 CR, 21 good PR) on central review. After a median follow-up of 1.56 years, 1-year local progression-free survival was 77.8%, with 1-year progression-free survival of 70.9%, 1-year overall survival of 93.3% and 1-year time to treatment failure of 57.6%. Grade 3 or 4 toxicity included mucositis (46.7%), dysphagia (46.7%), anorexia (42.2%), radiation dermatitis (26.7%), neutropenia (26.7%) and febrile neutropenia (4.4%). No treatment-related deaths were observed. Conclusions: This combination showed promising efficacy with acceptable toxicities. Further investigation in a phase III trial is planned.