We compared the outcomes of two different regimens - azithromycin and pseudoephedrine hydrochloride (PHCl) - for the treatment of otitis media with effusion (OME) in children. In a double-blind randomized clinical study, a total of 90 children aged between 2 and 13 years with persistent OME were randomly assigned to one of 3 treatment groups. The first group received azithromycin at a dose of 10 mg/kg once daily for 3 days and this regimen was repeated weekly for up to 12 weeks according to the results of tympanometry and pneumatic otoscopy. The second group received azithromycin at a dose of 10 mg/kg once daily for 3 days for the first week, and this regimen was repeated for 1 day a week for the following 11 weeks. The third group received PHCl, 4 mg/kg, 3 times daily for up to 12 weeks. Each patient underwent pneumatic otoscopic and tympanometric investigations at baseline and at Weeks 4, 8 and 12. The outcomes in the azithromycin-treated groups were superior to that in the decongestant group. However, the difference between the outcomes in the azithromycin groups according to the treatment protocol was not statistically significant. Azithromycin therapy, particularly a once-weekly regimen, helps patients to comply with treatment and also helps us to achieve good results with minimal therapy.