- Background: Information regarding the specific characteristics of bilateral acute otitis media (BAOM) versus unilateral acute otitis media (UAOM) is lacking. Objectives: To compare the epidemiologic, microbiologic, and clinical characteristics of BAOM with UAOM in children. Patients and Methods: 1026 children aged 3–36 months (61%, <1 year of age) with AOM were enrolled during 1995–2003. All patients had tympanocentesis and middle ear fluid (MEF) culture at enrollment. Clinical status was determined by a clinical/otologic score evaluating severity (0 = absent to 3 = severe, maximal score 12) of patient's fever and irritability and tympanic membrane redness and bulging. Multivariate logistic regression models were used to estimate the risk of BAOM and UAOM presenting with a high severity score (≥8). Results: Six-hundred twenty-three (61%) patients had BAOM. Positive MEF cultures were recorded in 786 (77%) patients. More patients with BAOM had positive MEF cultures than patients with UAOM (517 of 623, 83% versus 269 of 403, 67%; P < 0.01). Nontypable Haemophilus influenzae was more common in BAOM than in UAOM (390 of 623, 63% versus 170 of 430, 42%; P < 0.01). Overall, the clinical/otologic score showed higher severity in culture-positive than in culture-negative patients (8.2 ± 2.0 versus 7.7 ± 2.2; P < 0.001) and in BAOM than in UAOM (8.3 ± 2.1 versus 7.8 ± 2.1; P = 0.001). Clinical/otologic score of ≥8 was more frequent in BAOM than in UAOM patients (371, 61.8% versus 200, 51.3%; P = 0.001). The estimated risk for BAOM patients (compared with UAOM patients) to present with a score ≥8 was 1.5. The association between BAOM and clinical/otologic score ≥ 8 was maintained after adjustment for age, previous AOM history, and culture results at enrollment. Conclusions: (1) BAOM is frequent; (2) Nontypable H. influenzae is more frequently involved in the etiology of BAOM than of UAOM; (3) The clinical picture of BAOM is frequently more severe than that of UAOM, but overlap of clinical symptoms is common.