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International audience; Feed efficiency is one of the keystones that could help make animal production less costly and more environmentally friendly. Residual feed intake (RFI) is a widely used criterion to measure feed efficiency by regressing intake on the main energy sinks. We investigated rumen and plasma metabolomic data on Romane male lambs that had been genetically selected for either feed efficiency (line rfi−) or inefficiency (line rfi+). These investigations were conducted both during the growth phase under a 100% concentrate diet and later on under a mixed diet to identify differential metabolite expression and to link it to biological phenomena that could explain differences in feed efficiency. Nuclear magnetic resonance (NMR) data were analyzed using partial least squares discriminant analysis (PLS-DA), and correlations between metabolites’ relative concentrations were estimated to identify relationships between them. High levels of plasma citrate and malate were associated with genetically efficient animals, while high levels of amino acids such as L-threonine, L-serine, and L-leucine as well as beta-hydroxyisovalerate were associated with genetically inefficient animals under both diets. The two divergent lines could not be discriminated using rumen metabolites. Based on phenotypic residual feed intake (RFI), efficient and inefficient animals were discriminated using plasma metabolites determined under a 100% concentrate diet, but no discrimination was observed with plasma metabolites under a mixed diet or with rumen metabolites regardless of diet. Plasma amino acids, citrate, and malate were the most discriminant metabolites, suggesting that protein turnover and the mitochondrial production of energy could be the main phenomena that differ between efficient and inefficient Romane lambs.