BACKGROUND: Staphylococcus aureus is a common cause of bacteremia, yet the epidemiology, and predictors of poor outcome remain inadequately defined in childhood. METHODS: ISAIAH is a prospective, cross-sectional study of S. aureus bacteremia (SAB), in children hospitalized in Australia and New Zealand, over 24-months (2017-2018). RESULTS: Overall, 552 SABs were identified, (incidence 4.4/100,000/yr [95% confidence interval (CI) 2.2-8.8]), with methicillin-susceptible (84%), community onset (78%) infection predominating. Indigenous children (8.1/100,000/yr [CI 4.8-14.4]), those from lower-socioeconomic areas (5.5/100,000/yr [CI 2.8-10.2]) and neonates (6.6/100,000/yr (CI 3.4-11.7) were over-represented. Although 90-day mortality was infrequent, one-third experienced the composite of: length of stay >30 days (26%), ICU admission (20%), relapse (4%), or death (3%).Predictors of mortality included prematurity (aOR 16.8 [CI 1.6-296.9]), multifocal infection (aOR 22.6 [CI 1.4-498.5]), necrotizing pneumonia (aOR 38.9 [CI 1.7 - 1754.6]), multiorgan dysfunction (aOR 26.5 [CI 4.1-268.8]) and empiric-vancomycin (aOR 15.7 [CI 1.6-434.4]); whilst Infectious Diseases (ID) consultation (aOR 0.07 [CI 0.004-0.9]) was protective. Neither MRSA nor vancomycin trough-targets impacted survival; however, empiric-vancomycin was associated with significant nephrotoxicity (OR 3.1 [CI 1.3-8.1]). CONCLUSIONS: High SAB incidence was demonstrated, with at-risk populations identified for future prioritized care. For the first time in a pediatric setting, necrotizing pneumonia and multifocal infection were predictors of mortality, whilst ID consultation was protective. The need to re-evaluate pediatric vancomycin trough-targets and limit unnecessary empiric-vancomycin exposure, to reduce poor outcomes and nephrotoxicity is highlighted. One in three children experienced considerable SAB morbidity, therefore pediatric inclusion in future SAB comparator trials is paramount to improve outcomes.