Oral mucositis (OM) is a frequent and painful sequelae of concomitant chemoradiation (CRT) used for the treatment of head and neck cancer (HNC) for which there is no effective intervention. This randomized, placebo-controlled study evaluated the efficacy of a novel, mucoadhesive topical tablet formulation of clonidine in mitigating CRT-induced OM in HNC patients.Patients with HNC undergoing adjuvant radiotherapy (60-66 Gy; 5 x 1.8-2.2 Gy/wk) with concomitant platinum-based chemotherapy received daily local clonidine at 50 μg (n = 56), 100 μg (n =65) or placebo (n = 62) via a topical mucobuccal tablet, 1-3 days before and during treatment. The primary end point was the incidence of severe OM (SOM, WHO grade 3/4).SOM developed in 45% vs. 60 % (p = 0.06) of patients treated with clonidine compared to placebo and occurred for the first time at 60 Gy as opposed to 48 Gy (median; HR = 0.75 [95 % confidence interval (CI): 0.484; 1.175], p = 0.21); median time to onset was 45 vs. 36 days. Opioid analgesic use, mean patient-reported mouth and throat soreness, and CRT compliance were not significantly different between treatment arms. Adverse events were reported in 90.8% vs. 98.4%, nausea in 49.6% vs. 71.0%, dysphagia in 32.8% vs. 48.4% and reversible hypotension in 6.7% vs. 1.6% clonidine vs. placebo-patients, respectively.Although the primary endpoint was not met, the positive trends of OM-associated outcomes suggest that the novel mucoadhesive tablet delivery of clonidine might favorably impact the course and severity of CRT-induced SOM and support further evaluation.