Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. Recently, it has been suggested that an exaggerated immune response to fungi is crucial in the pathogenesis of the disease. On the basis of this hypothesis, intranasal treatment with amphotericin B should benefit patients with CRS. Data from 2 uncontrolled and 2 controlled trials are conflicting, however. To clarify the role of intranasal antifungal drugs in the treatment of CRS, we conducted a large, double-blind, placebo-controlled, multicenter study comparing the effectiveness of amphotericin B nasal lavages with placebo. A total of 116 randomly selected patients with CRS were instructed to instill 25 mL amphotericin B (100 microg/mL) or placebo to each nostril twice daily for 3 months. Primary outcomes included a reduction in total visual analog scale (VAS) score and nasal endoscopy score. Secondary outcome measures included peak nasal inspiratory flow, polyp score, quality of life (Short Form-36, Rhinosinusitis Outcome Measure-31), and individual VAS scores. Analysis was based on intention to treat and involved all patients randomly assigned. Mean VAS scores, Short Form-36 and Rhinosinusitis Outcome Measure-31 data, peak nasal inspiratory flow values, nasal endoscopy scores, and polyp scores were similar in both treatment groups at the time of randomization, and no significant differences were observed after 13 weeks of treatment. Amphotericin B nasal lavages in the described dosing and time schedule do not reduce clinical signs and symptoms in patients with CRS. Amphotericin B nasal lavages in the described dosing and time schedule are ineffective and therefore not advised in the treatment of patients with CRS.