Background: Platinum-based CRT is the treatment of choice for LAHNC, but induces a high rate of acute toxicity, including dysphagia and aspiration pneumonia. Aspiration pneumonia often requires hospitalization and negatively influences quality of life (QoL). We hypothesized that prophylactic antibiotics during CRT in LAHNC patients (pts) can prevent pneumonia and hospital admissions. Methods: A multicenter randomized trial was performed. The standard treatment group (STG) received standard care; the intervention group (IG) received prophylactic amoxicillin/clavulanic acid from day 29 until 14 days after completion of CRT. LAHNC pts treated with CRT were registered before start and randomized between day 21-28, unless they received antibiotics 14 days before planned randomization. The primary objective was to measure a reduction in the rate of pneumonias. A confirmed pneumonia was defined as a previously non-existing infiltrate on chest X-ray or ≥ 3 of the following features: sustained fever, rales or rhonchi on chest auscultation, sputum with substantial leukocytes or sputum culture showing a pathogen. A suspected pneumonia was defined as 2 of these features. Results: A total of 106 pts were registered, of which 94 pts were randomized: 48 pts were allocated to the STG and 46 pts to the IG. Pts were equally randomized by minimization for smoking, COPD status, HPV status in oropharyngeal cancer, degree of weight loss, primary tumor site, participating centre and tube feeding at time of randomization. A confirmed or suspected pneumonia during CRT and follow up till 3.5 months was observed in 20 (41.7%) of 48 pts in the STG, and 20 (43.5%) of 46 pts in the IG, respectively (P = 0.56). Hospitalization for any cause (i.e., fever, dehydration, mucositis or pneumonia), was necessary in 17 of 48 pts (35.4%) in the STG versus 9 of 46 pts (19.6%) in the IG (P = .08). Conclusions: Prophylactic antibiotics during CRT for LAHNC did not reduce the rate of pneumonias. However, there is a trend towards a reduced rate of hospitalizations, which potentially may lead to a better QoL and reduction in costs. Currently, further microbiological and cost-effectiveness analyses are being performed. Clinical trial information: NCT01598402