Oral mucositis is frequent but serious adverse event associated with radiotherapy or radiochemotherapy in head and neck cancer severely impairs health-related quality of life, leading to poor prognosis due to discontinuation of the therapy. Although a number of compounds have been tested for prophylaxis of oral mucositis, few of them are satisfactory. We investigated the effect of polaprezinc (zinc L-carnosine), a gastric mucosal protective drug, on radiochemotherapy-induced oral mucositis, pain, xerostomia and taste disturbance in patients with head and neck cancer. Patients were randomly assigned to receive polaprezinc (n = 16) or azulene oral rinse as the control (n = 15). The incidence rates of mucositis, pain, xerostomia and taste disturbance were all markedly lower in polaprezinc group than in control. Moreover, the use of analgesics was significantly (p = 0.003) less frequent and the amount of food intake was significantly (p = 0.002) higher in polaprezinc group than in control. On the other hand, tumor response rate in patients with neoadjuvant radiochemotherapy was not significantly affected by polaprezinc, in which the response rate (complete plus partial response) was 88% for polaprezinc and 92% for control (p = 1.000). Therefore, it is highly assumable that polaprezinc is potentially useful for prevention of oral mucositis and improvement of quality of life without reducing the tumor response.