OBJECTIVES: To compare direct and indirect costs of treating acute otitis media (AOM) using 5 antimicrobials. METHODS: 263 patients, mean age 35.2 months (SD 23.0), were enrolled from 6 primary care clinics in a prospective, randomized, naturalistic cost effectiveness trial. Inclusion criteria were age > 6 months and < 8 years, clinical diagnosis of AOM, physician requiring antimicrobial treatment, and no antimicrobial received within 30 days. Patients with allergies to the study antimicrobials were excluded. Direct costs included physician, clinic, laboratory, procedure charges, antimicrobials, ancillary medications, side effects and revisits. Indirect costs included travel, loss of parental income, and baby-sitter fees. After giving informed consent, patients were randomized to amoxicillin (N=53), amoxicillin/clavulanate (N=52), azithromycin (N=60), clarithromycin (N=48), or cefixime (N=50) treatment and followed for 30 days. Biweekly telephone surveys of patient caregivers and chart reviews were used to collect resource utilization data. RESULTS: Total cost of treatment was lowest with azithromycin, $130.85 (SD 79.50), and highest with cefixime, $180.69 (SD 90.48), p=0.081. Statistically significant differences among antimicrobial costs were observed; lowest mean cost was amoxicillin, $5.71 (SD 1.50) and highest was cefixime, $63.56 (SD 8.12), p=0.0001. Although not statistically significant, total direct costs of treatment were lower with azithromycin, $81.12 (SD 43.67) than amoxicillin, $94.32 (SD 59.43), p=0.69. CONCLUSIONS: Statistically significant differences in total costs between antimicrobials in treating AOM were not observed.