Understanding the biological basis of drug resistance and developing techniques which facilitate prediction of outcome have the potential to revolutionize the pharmacotherapy of epilepsy. We have performed a pilot study of metabonomic analysis using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) in an effort to identify metabolic biomarkers of response to antiepileptic drug treatment. Pre-treatment serum samples were obtained from 125 patients with newly diagnosed epilepsy who were taking part in a randomised monotherapy trial. Outcome (responder, non-responder) was assessed at 6 weeks, 6 months, and 12 months after starting treatment. Serum samples were subject to investigation by both NMR and MS and the resulting data interrogated by principal components analysis (PCA). There was no clear distinction in the metabolic profile, acquired by either NMR or MS, of responders and non-responders to AED treatment at any of the three clinical end-points investigated, suggesting that pre-treatment serum samples do not contain any prominent biomarkers of responsiveness to initial treatment in new-onset epilepsy. Metabonomic analysis is undoubtedly applicable to the search for biological predictors of response to drug treatment in epilepsy, but future studies should employ larger patient cohorts, more discriminatory analyses, and a less equivocal clinical phenotype.