Abstract Background Many publications have addressed the problem of weight gain and endocrine abnormalities in patients treated with sodium valproate (VPA). However, the presence of metabolic syndrome (MetS) among obese patients with epilepsy on VPA has received little attention. Methods Thirty-six patients receiving VPA monotherapy were included in this study to evaluate the presence of MetS. All patients were interviewed and clinically examined. Blood samples were obtained after an overnight fast, and an oral glucose-tolerance test was performed. Twenty-eight subjects who were obese but had no epilepsy and were otherwise well were collected as controls (“simple obesity” group). Results The two study groups were well matched in terms of age, gender and body mass index. Insulin resistance measured via homeostasis model assessment (HOMA) index was more severe among the VPA-treated group (4.91±2.91 vs. 2.00±1.72, P=0.007). The frequency of the MetS was slightly higher in the patients with epilepsy compared to controls (47.2% vs. 32.1%, respectively), but this difference was not statistically significant (P=0.223). Multivariate analysis with stepwise logistic regression revealed low positive correlations between MetS development, HOMA index (P=0.029; r=0.361) and valproic acid dose (P=0.049; r=0.323). These correlations were independent of other clinical parameters. Conclusions Our preliminary study suggests that obese patients with epilepsy treated with VPA are at higher risk of MetS than individuals who are “simply obese” but otherwise well. Therefore, the HOMA index should be monitored in obese patients who receive VPA therapy, rather than monitoring body weight alone.