Background: Although treatment guidelines for bipolar disorder in many countries commonly include lithium carbonate joint with sodium valproate, this combination is not effective for all patients. Moreover, some adverse reactions related to this treatment, neurotoxicity and interaction with other drugs justify and call for a new reviewing of the issue. Methods: Evidence base for the interactions of combined drugs, the metabolic features, action mechanism, efficacy and side effects of these treatment combinations were reviewed. Considerable attention was given to the relationship of the mutual action of these drugs with their clinical efficacy but also their side effects. Results: The efficacy of combination therapy of lithium with valproate for treatment and prevention of mania were superior to monotherapy of lithium or valproate. Conclusion: Double mood stabilizer therapy is the best relative treatment for patients with bipolar disorder, especially mania and related episodes.