OBJECTIVE To determine whether lamotrigine affects serum concentrations of valproic acid. METHODS Pre-morning-dose serum valproic acid concentrations were measured in 76 subjects with epilepsy (48 M, 28 F, age range 6-20 years, mean age 14 years) in whom lamotrigine was added while the dose of valproate and other medication remained unchanged. In a comparison group, either acetazolamide or gabapentin was added to sodium valproate. RESULTS Far more subjects (26/76 = 34%) had an increase of >25% in valproic acid concentration with lamotrigine than those who had a decrease of >25% (4/76 = 5.3%). The mean valproic acid concentration before starting lamotrigine was 61.0 mg/L and on lamotrigine was 67.1 mg/L; the difference in means was 6.1 mg/L (standard error 2.1, 95% confidence limits 2.0, 10.2, p=0.004, highly significant, paired sample t-test, two-tailed), a rise of 10%. The change in valproic acid concentration appeared to depend on the initial valproic acid concentration (Pearson r=-0.405, p<0.001). In 14.5% of the subjects the increase in valproate concentration was >50%, which could lead to toxicity, although the increase tended to occur with lower or intermediate initial valproic acid concentrations whereas a small overall decrease in valproic acid concentrations with lamotrigine was found with the higher initial valproic acid concentrations. One subject had abnormal bruising with the increased valproate level after lamotrigine was added, which resolved on decreasing the valproate dose. The changes in valproic acid concentrations in the comparison group were small (mean increase 2.6%) and were not statistically significant. CONCLUSIONS Although there is a wide variation in the changes of valproic acid concentrations when lamotrigine is added, the concentrations tend to increase rather than decrease, especially with low or intermediate initial valproic acid concentrations. In some cases valproate toxicity, manifested by abnormal bruising, may result, although at higher initial valproic acid concentrations the valproic acid concentration usually tends to fall slightly with the addition of lamotrigine.