<h3>Purpose/Objective(s)</h3> Local recurrences of squamous cell carcinomas of the head and neck are often located within the primary tumor volume, suggesting radio-resistance. Targeting dose escalation to radio-resistant sub-volumes within the primary tumor might increase tumor control as well as toxicity risks. Adaptive radiotherapy could limit these risks by improving dose painting precision. This hypothesis was tested in the Adaptive Radiation Treatment for Head and Neck Cancer (ARTFORCE) trial (NCT01504815); a multicenter randomized phase III trial evaluating a 18F-FDG PET/CT-guided dose painting and a scheduled adaptation strategy in locally advanced squamous cell carcinomas of the head and neck (LAHNSCC). Here, the first acute toxicity analysis will be presented. <h3>Materials/Methods</h3> A total of 222 patients with LAHNSCC scheduled for chemoradiotherapy were randomized: 109 patients in the experimental arm (A) and 113 in the standard arm (B). In arm A, a boost (min 70Gy, max 84Gy, mean 77Gy) was targeted at the PTV-PET: a 3mm expansion of the sub-volume within the primary tumor with PET-SUV ≥ SUV50%. Irradiation was performed in 35 fractions by simultaneous integrated boost technique. In this arm, two strategies were used to contain toxicity risks. First, the PTV surrounding PTV-PET received a slightly lower dose with a mean of 67Gy (min 64Gy, max 70Gy). Secondly, delineations were adjusted at the 10<sup>th</sup> fraction for obvious anatomical changes. Patients in arm B were treated by conventional radiation treatment with a homogenous dose of 70Gy in 35 fractions. The doses to the pathological lymph nodes and nodal volumes were identical for both arms; 70Gy and 54.25Gy, respectively. Acute toxicities were scored according to the CTCAE v4.0 and defined as toxicities occurring during treatment until 90 days after treatment or until 110 days after treatment if these immediately subsided after 110 days. For statistical analysis, maximum CTCAE grades were dichotomized three times: ≥ grade 2, ≥ grade 3 and ≥ grade 4. Fisher's exact test was then used to detect statistical differences between the two study arms using a level of significance of 0.05. <h3>Results</h3> No statistically significant differences (p ≥ 0.11) in acute toxicity rates between both study arms were observed. Most common reported grade ≥3 toxicities were mucositis (62% in arm A versus 57% in arm B, p = 0.41), dysphagia (53% versus 54%, p = 1), hematologic toxicities (21% versus 26%, p = 0.43) and radiation dermatitis (18% versus 16%, p = 0.72). Half of the reported grade 4 toxicities were due to hematologic toxicities (6% versus 7%, p = 1). Grade 4 mucositis presented twice in both arms. One patient in arm A and two patients in arm B developed grade 4 dysphagia. One patient in arm A died due to aspiration pneumonia. No other grade 5 toxicities were reported. <h3>Conclusion</h3> The results of this analysis suggest that this dose painting and adaptive radiotherapy strategy preserves acute toxicity rates while increasing dose to radio-resistant sub-volumes.