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Background It has traditionally been considered that mother-infant ABO incompatibility only causes mild haemolytic disease of the newborn (HDN). However, this view is inconsistent with clinical practice, and large-scale population-based data are lacking to investigate its effects on neonates.Methods Differences in hospitalisation rates and incidence rates of neonatal hyperbilirubinaemia (NHB) and anaemia among 47 679 Chinese liveborn neonates with different mother-infant ABO combinations, differences in the incidence of ABO-incompatible HDN (ABO-HDN) among neonates with O-B versus O-A mother-infant ABO incompatibility, and the contributions of ABO-HDN to the development of NHB and neonatal anaemia were analysed.Results Of the 47 679 liveborn neonates, neonates with mother-infant ABO incompatibility had higher rates of hospitalisation and incidence of NHB and anaemia. The hierarchy of the risk of mother-infant ABO incompatibility to the neonate was O-B > O-A > non-O-A/O-B incompatibility. Among neonates with O-B and O-A mother-infant ABO incompatibility, the ABO-HDN incidence rates were 15.27% (513/3359) and 11.33% (417/3680), respectively (95% CI 1.41 (1.23 to 1.62)), and the severe ABO-HDN incidence rates were 2.05% (69/3359) and 1.14% (42/3680), respectively (95% CI 1.82 (1.23 to 2.67)). Among the 7039 neonates with O-A/O-B mother-infant ABO incompatibility, ABO-HDN was an independent aetiological factor in 41.11% (666/1620) of the neonates with NHB, 70.27% (52/74) of the neonates with severe NHB, 42.34% (163/385) of the neonates with anaemia and 18.28% (17/93) of the neonates with severe anaemia.Conclusions Mother-infant ABO incompatibility often leads to severe HDN and is a dominant cause of NHB and neonatal anaemia, leading to significantly higher neonatal hospitalisation rates.