Rationale Previous functional imaging studies have shown altered brain activity during cognitive task performance in bipolar patients. However, the fact that these patients are often on medication makes it unclear to what extent these changes reflect treatment effects. Objectives This study aims to identify regional brain activity changes occurring following lithium and valproate treatment in healthy volunteers. Methods This was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n ΒΌ 12), 900 mg lithium (n ΒΌ 9), or placebo (n ΒΌ 12). Functional images were acquired using functional magnetic resonance imaging (fMRI) while subjects performed three cognitive tasks, a word generation paradigm, a spatial attention task and a working memory task. fMRI was carried out both before and after 14 days of treatment with valproate, lithium or placebo. The changes in the magnitude of the blood-oxygen-level-dependent (BOLD) signal after treatment were compared between the groups using a one-way ANOVA for each task followed by a post-hoc multiple comparisons correction. Results A significant group effect was noted in the change in BOLD signal magnitude from baseline to post-treatment, in all three tasks (working memory p < 0.000; spatial attention task p ΒΌ 0.003; word generation paradigm p ΒΌ 0.030). In the working memory task, the lithium group had a significant decrease in BOLD signal change, compared with the control group ( p < 0.000). A decrease in BOLD signal change was also noted in the valproate group, in the spatial attention task ( p ΒΌ 0.004). Both lithium and valproate groups had a decreased BOLD signal in the verbal task, following treatment, compared with the placebo group ( p ΒΌ 0.061 (lithium approached significance); p ΒΌ 0.050 (valproate)). Conclusions These findings suggest that lithium and valproate have independent effects on brain activation that vary in a task and region-dependent manner.