BACKGROUND: This study evaluated the efficacy of fluconazole prophylaxis in reducing radiation-induced oral mucositis (RIOM) and Candida carriage in head and neck cancer (HNC) patients undergoing concurrent chemoradiotherapy (CCRT). METHODS: A prospective, double-blinded, randomized controlled trial was conducted with 78 HNC patients receiving either fluconazole (100 mg daily) or placebo during CCRT. The primary outcome was the incidence of grade 2 or higher RIOM. Secondary outcomes included positive Candida cultures and colony-forming units (CFUs). Mixed-effects ordinal logistic regression and logistic regression were used for analysis. RESULTS: Fluconazole significantly reduced the incidence of grade 2 or higher RIOM at week 7 (p = 0.039), positive Candida carriage at week 4 (p = 0.024) and week 7 (p = 0.029), and median CFUs at week 7 (p = 0.050). CONCLUSIONS: Fluconazole significantly reduces RIOM severity and Candida colonization in HNC patients undergoing CCRT, suggesting its efficacy as a prophylactic treatment.