Background/Aim: We evaluated the efficacy and compliance of a therapeutic approach based on intranasally-administered hyaluronic acid (HA) in the treatment of chronic otitis media with effusion (OME) in pediatric patients. Materials and Methods: Forty-four pediatric patients were enrolled and randomized into two groups: the first one (Group A) received a treatment based on HA and Group B was treated with saline solution only. Both therapies were intranasally administered by compressed-air nebulizer and Rinowash, a nebulizer designed to treat the upper airway structures. Patients were evaluated by medical history, otoscopy, pure-tone audiometry, and impedentiometry at 0 (T0), 4 (T1), 12 (T2), and 16 (T3) weeks. Results: The analysis of tympanometric and audiometric data, such as the evaluation of otoscopic improvements, showed significant differences between the two groups. After just 1 month of therapy, (T1) tympanometric evaluation showed greater improvements in Group A. Data on the audiometric threshold improvements, measured at different stages of the treatment, showed a greater improvement of the mean/median value of the auditory thresholds in patients treated with HA than in patients of Group B. Conclusion: The absence of side effects and the results observed make this therapeutic approach a potential valid alternative in the difficult long-term management of OME.