Radiotherapy-related mucositis is the most frequent complication in the patients submitted to irradiation for head and neck cancers. Many such patients may develop mycotic infections which may lead to treatment discontinuation, with possible consequences on the local control of these cancers. In this study, we investigated the efficacy of fluconazole in preventing mycotic mucositis in 80 patients undergoing radiation therapy for head and neck cancers. The patients were randomized to two groups: 41 patients in group A received the supporting treatment we usually administer, plus fluconazole (50 mg/day) starting from the 6th irradiation session throughout the treatment; 39 patients in group B received the same baseline treatment, but were given the drug only when mycotic infections appeared. The clinical characteristics, treated sites, treatment doses and volumes were similar in the two groups of patients. Fluconazole was well tolerated and no early or late toxicity was observed. We had 1 mycotic mucositis and 14 non-scheduled treatment discontinuations in group A, vs. 19 and 30, respectively, in group B. Radiation therapy lasted 52.3 days (mean) in group A and 55.6 days (mean) in group B; the differences were statistically significant. In our experience, fluconazole, used prophylactically from the 6th radiotherapy session on, reduced the number of mycotic infections and improved radiotherapy schedule in our head and neck cancer patients.