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Objective: To estimate the contribution of infections to childhood deaths in England and Wales over a 3-year period., Design: Retrospective analysis of national electronic death registration data., Setting: England and Wales., Patients: Children aged 28 days to 15 years who died during 2013-15., Main Outcome Measures: The proportion of children who died of infection compared with total deaths over 3 years; the main pathogens responsible for infection-related deaths in different age groups; comparison with similar data from 2003 to 2005., Results: There were 5088 death registrations recorded in children aged 28 days to <15 years in England and Wales during the three calendar years, 2013-2015 (17.6 deaths/100 000 children annually) compared with 6897 (23.9/100 000) during 2003-05 (incidence rate ratios (IRR) 0.74, 95% CI 0.71 to 0.77). During 2013-15, there were 951 (18.7%, 951/5088) infection-related deaths compared with 1368 (19.8%, 1368/6897) during 2003-05, equivalent to an infection-related mortality rate of 3.3/100 000 compared with 4.8/100 000 during the two periods (IRR 0.69, 95% CI 0.64 to 0.75), respectively. An underlying comorbidity was recorded in 55.0% (523/951) of death registrations during 2013-15 and increased with age. Where recorded, respiratory tract infection was the most commonly reported presentation (374/876, 42.7%) during 2013-15. Central nervous system infections accounted for only 4.8% (42/876). Overall, 63.1% (378/599) of infection-related deaths were associated with a bacterial, 34.2% (205/599) with a viral and 2.5% (15/599) with a fungal infection., Conclusions: Beyond the neonatal period, all-cause and infection-related childhood mortality rates have declined by 26% and 31%, respectively, over the past decade. However, infection continues to contribute to one in five childhood deaths., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)