Background: Long-term toxicity is highly relevant for cancer survivors. Therefore, in a clearly defined patient population with HNSCC individualized risk-adapted De-intensification of radiotherapy(RT) should be investigated to reduce long-term toxicity without compromising locoregional control rates (LRRR). Methods: Patients with newly diagnosed HNSCC after surgery with the following tumor stages (TNM 7th Edition) were eligible for the study: Oral cavity, oropharynx, larynx: pT1-3, pN0-pN2b. Hypopharynx: pT1-2; pN1, resection margin (R) ≥1mm, cM0.Patients were treated in 3 different arms adapted to tumor stage and quality of surgery performed (table below). Concomitant chemotherapy was applied according to standard. Primary endpoint was the LRRR after 2 years (y). After 2y a LRRR up to 10% was expected and an additionally LRRR in non-irradiated or dose-reduced areas of 6% would be accepted. The calculated sample size was 150 patients. Secondary endpoints were overall(OS)/ disease-free(DFS) survival and late toxicity according to CTC-AE v4.0. Results: Between Oct 2014 and March 2021 150 patients were enrolled. 8 (5%) patients were treated in arm A, 88 (59%) in arm B and 54 (35%) in arm C. Median age was 59 years. Tumor localisation was: 35% oral cavity, 63% oropharynx (82% HPV-positive), 1% Hypopharynx, 1% Larynx. 61 patients (41%) were stage IVA, 81 (54%) stage III and 8(5%) stage II. Median follow up was 36 months. LRRR after 2 and 3y was 6% (95%-CI 2-10%), and 7% (CI 3-12%). LRRR in not irradiated or dose-reduced regions was 4 % (CI 1-7%) after 2 and 5 % (CI 1-9%) after 3y. The 2 and 3y DFS rates were 90% (CI 85-95%) and 88% (CI 82-94%) and the OS rates were 94% and 94% (CI 90-98%). Late dysphagia was as follows: 0°: 55%, I°: 29%, II°: 9%, III°: 3%. Other grade ≥3 toxicities: Xerostomia 1%, esophageal stenosis 2%, osteonecrosis of the mandible 1%. Conclusions: The trial met its primary endpoint. De-intensification of RT independent of HPV status in a pre-defined low-risk patient population is safe and results in very low rates of late toxicity. Clinical trial information: NCT02528955.