Acute otitis media (AOM) is a common and important source of morbidity in children, although most cases resolve spontaneously. While frequently recommended, decongestant and antihistamine therapy is of unclear benefit. To determine the efficacy of decongestant and antihistamine therapy in children with AOM on outcomes of AOM resolution, medication side effects, and complications of AOM. Comprehensive search of Cochrane's Controlled Trials Registry, Medline and Embase was conducted. Bibliographic review and requests for information from study authors and pharmaceutical companies supplemented this. Randomized controlled trials evaluating decongestant (DC) or antihistamine (AH) treatment for children with AOM were included. Patient-oriented outcomes were considered most relevant. There were no quality or language restrictions. Investigators independently evaluated studies for inclusion, performed validity assessments, and completed data extraction. Dichotomous data were pooled to generate relative risks and numbers needed to treat, and homogeneity was assessed using approximate chi-square tests. For the combined control groups, healing rates at 2 weeks were high, with rates of persistent AOM <23%. No additional benefit was demonstrated from intervention subgroupings DC, AH, or any medication (DC and/or AH). Only the combined treatment (DC + AH) group demonstrated statistically lower rates of persistent AOM at the 2-week period (RR 0.76, 95% CI, NNT 10.5, 95% CI). No benefit was found for other outcomes including early or late cure rates, symptom resolution, prevention of surgery or other complications. There was an increased risk of medication side effects for those receiving an intervention, which reached statistical significance for the "any medication" and decongestant groupings (NNH 16.6, 14.3 respectively, 95% CI ). Validity subanalyses demonstrated that lower quality studies found benefit, but analysis of those studies with higher validity scores found no benefit to treatment. Given lack of benefit and increased risk of side effects, these data do not support the use of decongestant, antihistamine, or combined DC/AH treatment in children with AOM. The small statistical benefit found in the combination medication group is of small clinical significance and study design may be biasing the results.