BACKGROUND: We analyzed the demographic and risk factors, middle ear fluid (MEF) pathogens, pneumococcus serotype distribution, and bacterial antibiotic non-susceptibility among children with uncomplicated acute otitis media (uAOM) and complex AOM (cAOM) over three timeframes: 2006-2009 (PCV7 era), 2010-2014 (early-PCV13 era), and 2015-2023 (late-PCV13 era). METHODS: 1,537 children were enrolled over 18 years and prospectively followed from 6-36 months of age. Upon diagnosis of AOM, tympanocentesis was performed for MEF collection and culture. Electronic medical records were analyzed to identify uAOM and cAOM episodes. RESULTS: Analysis of demographic data showed that male sex, family history of AOM, and daycare attendance increased the odds of developing cAOM compared to uAOM. Streptococcus pneumoniae was less likely in cAOM, and Haemophilus influenzae more likely as compared to uAOM. AOM caused by S. pneumoniae decreased significantly in the early-PCV13 and late-PCV13 eras. This was driven by decreases in cAOM caused by PCV13 S. pneumoniae strains, especially serotype 19A. S. pneumoniae penicillin non-susceptibility was associated with cAOM and reduced in the early-PCV13 era. DISCUSSION: The risk factors for developing cAOM compared to uAOM are similar. PCV13 significantly reduced cAOM and penicillin non-susceptibility associated with S. pneumoniae, driven by reduction in cases caused by serotype 19A. H. influenzae continued to be a dominant cause of cAOM. Although non-PCV13 S. pneumoniae serotypes emerged in the late-PCV13 era, the lower level of cAOM caused by S. pneumoniae was sustained.