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The aim of this study was to elucidate the effects of a very low-calorie diet and weight loss on the serum and fecal metabolome and the potential of the metabolome to predict inter-individual differences in body weight loss. NMR-based metabolomics was carried out on serum and fecal samples obtained from healthy female subjects ( n = 56; Age: 46.33 ± 10.39 years; BMI 28.32 ± 1.55 kg/m) pre- and post-weight reduction. An elevated level of 3-hydroxybutyric acid (3-HBA) and acetoacetate and decreased levels of lipoproteins, cholines and glucose were identified in serum after the weight reduction. In the fecal metabolome, a decreased level of short-chain fatty acids was observed after the weight reduction. The body weight for each individual at pre- and post-intervention was linked to the level of lipoproteins in serum (VLDL, p = 0.039; LDL, p = 0.023) and serum 3-HBA ( p < 0.001), and a tendency for a similar relation was found for the fecal concentration of acetate ( p = 0.06) and propionate ( p = 0.075). The study demonstrates that the serum and fecal metabolome is affected by weight loss and that it includes information about inter-individual differences at the post-genomic level that may be of importance for the ability to undergo a weight loss. [ABSTRACT FROM AUTHOR]