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Background: Septic shock is the most severe phase of sepsis and is associated with high rates of mortality. However, early stage prediction of septic shock outcomes remains difficult. Metabolomic techniques have emerged as a promising tool for improving prognosis., Methods: Orthogonal projections to latent structures-discriminant analysis (OPLS-DA) models separating the serum metabolomes of survivors from those of non-survivors were established with samples obtained at the intensive care unit (ICU) admission (H0) and 24 h later (H24). For 51 patients with available H0 and H24 samples, multi-level modeling was performed to provide insight into different metabolic evolutions that occurred between H0 and H24 in the surviving and non-surviving patients. Relative quantification and receiver operational characteristic curves (ROC) were applied to estimate the predictability of key discriminatory metabolites for septic shock mortality., Results: Metabolites that were involved in energy supply and protein breakdown were primarily responsible for differentiating survivors from non-survivors. This was not only seen in the H0 and H24 discriminatory models, but also in the H0-H24 paired models. Reanalysis of extra H0-H24 paired samples in the established multi-level model demonstrated good performance of the model for the classification of samplings. According to the ROC results, nine discriminatory metabolites defined consistently from the unpaired model and the H0-H24 time-trend change (Δ H24-H0 ) show good prediction of mortality. These results suggest that NMR-based metabolomic analysis is useful for a better overall assessment of septic shock patients., Conclusions: Dysregulation of the metabolites identified by this study is associated with poor outcomes for septic shock. Evaluation of these compounds during the first 24 h after ICU admission in the septic shock patient may be helpful for estimating the severity of cases and for predicting outcomes., Trial Registration: All human serum samples were collected and stored, provided by the "center of biologic resources for liver disease", in Jean Verdier Hospital, Bondy, France (BB-0033-00027).