BACKGROUND: Vitamin E is a nutrient with both antioxidant and non-antioxidant activities and has been shown to modulate the function of a number of cell types in vitro and in human studies. However studies have also shown vitamin E to have detrimental interactions and therefore it is important to establish the extent to which this nutrient influences metabolism. Metabolomics can potentially identify nutrient-metabolism interactions and therefore the aim of this study was to use a non-targeted metabolomic approach to identify changes to the plasma metabolome following vitamin E supplementation in humans. METHODS: A relatively homogenous healthy adult male population (n = 10) provided a fasting blood sample immediately before and after a 4-week vitamin E supplementation regime (400 mg/d of RRR-α-tocopheryl acetate)) on top of their habitual diet. Plasma samples were analysed for vitamin E and clinical markers. Plasma underwent non-targeted metabolite profiling using liquid chromatography/mass spectroscopy and data was processed using multivariate statistical analysis. RESULTS: Plasma vitamin E concentrations were significantly increased following supplementation (p < 0.001). A partial least squares-discriminant analysis (PLS-DA) model was able to discriminate between samples taken pre and post vitamin E supplementation (goodness of fit R2Y = 0.82, predictive ability Q2 = 0.50). Variable influence on projection and PLS-DA loadings highlighted a number of discriminating ions that were confirmed as discriminatory through pairwise analysis. From database searches and comparison with standards these metabolites included a number of lysophosphatidylcholine species (16:0, 18:0, 18:1, 18:2, 20:3 and 22:6) that were increased in intensity post supplementation by varying degrees from 4% to 29% with the greatest changes found for lysoPC 22:6 and 20:3. CONCLUSIONS: Although a small scale study, these results potentially indicate that vitamin E supplementation influences phospholipid metabolism and induces lysoPC generation; a general pro-inflammatory response. Moreover the study identifies novel areas of vitamin E interactions and highlights the potential of metabolomics for elucidating interactions between nutrients and metabolic pathways in nutritional research.