- Background: Pneumococcal acute otitis media (AOM) has been previously considered as a more severe disease than that caused by other otopathogens, based on clinical and/or otologic scores. We sought to test this hypothesis in the pneumococcal conjugated vaccine (PCV) era. Methods: Children <6 years who presented with "severe" AOM episodes with middle ear fluid (MEF) cultures during 2008-2013 were retrospectively identified. "Severe" AOM episodes were considered if tympanocentesis was required, or if spontaneous otorrhea was present. Data were extracted for demographics, clinical and laboratory tests. Children were categorized according to their PCV status as "unimmunized" or "PCV7/PCV13 immunized", and according to their MEF culture results into the "pneumococcal" or the "non-pneumococcal" group. Leukocytosis was defined as white blood cells (WBC) count >15,000/μL, and elevated C-reactive protein (CRP) level was considered as >50 mg/L. Results: Of 295 eligible AOM episodes, 106 (36%) were culture positive. Children in the pneumococcal group (65, 61%) had a significantly higher WBC counts and higher CRP levels, were more often <2 years old and were more prone to complicate with acute mastoiditis (AM), compared to children in the non-pneumococcal group, p=0.03, p=0.02, p=0.04 and p=0.03, respectively. In the pneumococcal group, unimmunized children had higher WBC counts when compared with PCV13 immunized children (p=0.04), but there were no appreciable differences in CRP levels between unimmunized and PCV7/PCV13 immunized children. Conclusion: Pneumococcal AOM is associated with higher leukocytosis and CRP levels than non-pneumococcal AOM. Circulating Streptococcus pneumoniae strains causing "severe" AOM in PCV13 immunized children yielded lower inflammatory responses when compared with unimmunized children.