Purpose Anti-epileptic drugs (AEDs) and the ketogenic diet (KD) are often used concomitantly in children with refractory epilepsy. It has been hypothesised that certain AEDs may interfere with KD. The purpose of this study was to elucidate relationships between efficacy of KD and use of specific AEDs. Methods A retrospective study was performed in 71 children with refractory epilepsy starting the KD between 2008 and 2014 in Erasmus University Hospital Sophia Children's Hospital. Efficacy of the KD (defined as 50% seizure reduction) was evaluated after three months of treatment and related to the AEDs used. Results The KD was successful after three months in 61% of the children (N = 71). Efficacy was significantly reduced if children (n = 16) used lamotrigine (31%) at diet initiation or in the course of the diet, compared to other antiepileptic drugs (69%) (p = 0.006). In comparison to children using other antiepileptic drugs, the percentage of children that had adequate ketosis was significantly reduced in case of lamotrigine use (p = 0.049). Conclusion Lamotrigine treatment during KD is associated with a decreased efficacy of the KD. © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.