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Introduction Metabolomics may identify biological pathways predisposing children to the risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in infancy and overweight in early childhood in four European birth cohorts. Methods Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood was defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed-effect models and controlling the false discovery rate (FDR) at 5%. In addition, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth. Results In the Metabolome-Wide Association Study analysis, we identified three and eight metabolites associated with rapid growth and overweight, respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, were predictive of rapid growth (p = 1.6 x 10(-3)). Lower levels of the branched-chain amino acid (BCAA) valine (p = 8.6 x 10(-6)) were predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared with 0.69 and 0.69, respectively, for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P < 0.05) with rapid growth and overweight, respectively. The BCAA leucine, remained associated (1.6 x 10(-3)) with overweight after FDR correction. Conclusion The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understanding of mechanisms involved in postnatal growth. Cholestenone and BCAAs are suggestive of a role of the gut microbiome and nutrient signalling respectively in child growth trajectories. ; This research was supported by European Commission Horizon 2020 Grant to the 'STOP Project' (Grant ref. 774548). This study was funded by the European Union Social Fund and the Hellenic Ministry of Health ("Programme of prevention and early diagnosis of obesity and neurodevelopment disorders in preschool-age children in the prefecture of Heraklion, Crete, Greece' MIS number 349580, NSRF 2007-2013). Additional funding from the National Institute of Environmental Health Sciences (NIEHS) supported Dr. Chatzi (R01ES030691, R01ES029944, R01ES030364, R21ES029681, R21ES028903 and P30ES007048). The ENVIRONAGE birth-cohort is supported by the EU Program 'Ideas' (ERC-2012-StG-310898) and the FWO (G082317N), a PhD fellowship of the Bijzonder Onderzoeksfonds (BOF) at Hasselt University supported MD Alfano. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, 'Centro de Excelencia Severo Ochoa 2013-2017", SEV-2012-0208 and 'Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya' (2017SGR595). O.R. was supported by a UKRI Future Leaders Fellowship (MR/S03532X/1).