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Plasma samples were collected from 30 ONFH patients and 30 normal subjects. The global metabolomic profile was obtained through a combination of high\u2010throughput liquid\u2010 and gas\u2010chromatography\u2010based mass spectrometry analyses. All statistical analyses were conducted using the R software. The results showed clear differences in the metabolomic signature between the plasma of ONFH patients compared with normal subjects. Among the 354 identified metabolites, the expression of 123 metabolites were significantly changed in ONFH patients compared with normal subjects (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05, <jats:italic>q<\/jats:italic>\u2009&lt;\u20090.10). Bioinformatics analysis revealed that these abnormal metabolites were mainly involved in lipid\u2010, glutathione\u2010, nucleotide\u2010, and energy\u2010associated pathways, which might be related to enhanced inflammation, oxidative stress, and energy deficiency due to ONFH. This study provides the first metabolomic analysis of ONFH, and identifies a previously unrecognized metabolic signature in ONFH plasma. The results offer new insights into the pathological mechanisms of ONFH through its influence on metabolic pathways, providing the requisite framework for identifying biomarkers or novel targets for therapeutic intervention. \u00a9 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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