OBJECTIVE To determine the efficacy of a short course of an adrenocorticosteroid agent (prednisolone) given with amoxicillin as compared with that of amoxicillin alone for the treatment of chronic middle ear effusion (MEE). The efficacy of 2 weeks versus 4 weeks of amoxicillin with and without steroid was also assessed. METHODS In a double-blind, randomized trial, children who were 1 to 9 years of age and had MEE of at least 2 months' duration were assigned to 1 of 4 treatment arms: 1) steroid + amoxicillin for 14 days, then amoxicillin for 14 more days; 2) steroid + amoxicillin for 14 days, then placebo for amoxicillin for 14 more days; 3) placebo (for steroid) + amoxicillin for 14 days, then amoxicillin for 14 more days; or 4) placebo (for steroid) + amoxicillin for 14 days, then placebo for amoxicillin for 14 more days. Children were examined by otoscopy, tympanometry, and audiometry at entry and 2 and 4 weeks after entry; those without MEE at the 4-week visit returned monthly for up to 3 more visits or until recurrence of effusion. Serum immunoglobulin (Ig) G, IgM, IgA, and varicella titers were obtained at entry, and allergy skin testing was performed at the 4-week visit. RESULTS A total of 144 children was entered; 135 children (94%) returned for the 2-week visit, and 132 (92%) were seen for the 4-week visit. At the 2-week visit, 33.3% of children in the steroid + amoxicillin group had no MEE compared with 16.7% in the placebo + amoxicillin group (95% confidence interval for the difference in proportions: 2.4%-31.0%). At the 4-week visit, the percentage of children with no MEE in the steroid-treated group was 32.8%, whereas that in the placebo group was 20.0% (95% confidence interval for the difference in proportions in the 2 groups: -2.0%-27.7%). Comparing change in middle ear status from the 2- to the 4-week visit, there were no significant differences in recurrence of MEE or additional clearance of MEE between those who were treated with amoxicillin for 2 weeks and those who were treated for 4 weeks. By the 4-month visit, 68.4% of children who were in the steroid group and had no MEE at the 4-week visit had recurrence of MEE as did 69.2% of such children in the placebo group. A total of 126 (87.5%) children underwent allergy skin testing. Of the 122 children who had a positive reaction to histamine, 51 (41.8%) had 1 or more positive reactions to the test allergens. There was no difference in response to treatment between those with positive allergy tests and those without. CONCLUSIONS There was a significant difference in the proportion of children who were effusion-free immediately after 14 days of treatment with steroid and amoxicillin compared with those who were treated only with amoxicillin for 14 days. Within 2 weeks of finishing treatment, there was no longer any significant difference between the 2 groups regardless of whether amoxicillin was continued or not. Therefore, we conclude that treatment with the dose and type of steroid used in this study should not be universally recommended for treatment of chronic otitis media with effusion, and treatment with amoxicillin, if used, should not continue beyond 14 days.