- Background: The objective of this study was to determine the association between early bacteriologic failure and clinical failure in acute otitis media (AOM). Methods: Children with AOM aged 3–35 months enrolled in studies documenting both bacteriologic outcomes by tympanocentesis on day 4–6 and clinical outcomes on day 11–16 (immediate posttreatment visit) constituted our study group. Bacteriologic outcomes were studied for children with AOM caused by Streptococcus pneumoniae, nontypeable Haemophilus influenzae or both. The relative risk (RR) for clinical failure of children with bacteriologic failure compared with children with bacteriologic eradication was the main outcome measure. Results: Nine hundred seven episodes were analyzed. Clinical failure occurred in 7.3% of 660 patients with bacterial eradication versus 32.8% of 247 patients with bacteriologic failures. The overall RR (95% confidence interval) for clinical failure was 4.41 (95% CI: 3.19–6.11), with little variation between pathogens. After correction for age, gender, ethnic origin, previous otitis history, and previous antibiotic treatment, the rate was 6.52 (95% CI: 4.26–9.99). Across clinical studies with 8 antibiotic drug regimens for AOM, the rate of clinical failure correlated with bacteriologic failure (r = 0.8967; P = 0.003). Conclusions: In young children with culture-positive AOM, failure to eradicate the pathogen from middle ear fluid within the first few days of treatment leads to a significant risk for clinical failure.