This study was undertaken in 2 parts to investigate the relationship between body size and insulin resistance during treatment with valproic acid in children. The cross-sectional part revealed differences in terms of body size and homeostasis model assessment of insulin resistance, which were higher in the group on medication. The longitudinal part showed a major increase in body size and insulin resistance during the first year of therapy. There was a subsequent decrease in insulin resistance in association with the rise of body size, however with a trend to level off. These results might be helpful to enhance the knowledge of valproic acid action on both insulin resistance and weight gain, allowing to plan appropriate approach for the prevention of the consequences of the treatment with valproic acid.