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Background: Hypertonic saline inhalation has been shown to be effective in patients with cystic fibrosis and lung disease. However, adverse events including marked airway narrowing are reported and a bronchodilator must be given before the administration of the product. Methods: We carried out a prospective, randomized, double-blind, parallel-group, controlled study of a hypertonic saline solution containing hyaluronic acid (Hyaneb) versus standard hypertonic saline therapy to assess whether the presence of hyaluronic acid would improve the tolerability of hypertonic saline. Results and conclusions: The results showed that nebulized Hyaneb was more effective in reducing the need for β 2 bronchodilators and caused a significant reduction in the incidence of adverse effects compared with nebulized hypertonic saline solution alone. Its safety profile indicates that Hyaneb can be used for the treatment of lung disease in cystic fibrosis.