Although lithium and carbamazepine used alone are effective in treating acute mania, some patients do not respond adequately to either of these medications used alone. We assessed, under double-blind conditions, a potential synergism between carbamazepine and lithium in the acute treatment of mania. Six of 7 manic patients who had previously been largely refractory to lithium alone, and who still showed substantial mania after several weeks of double-blind treatment with carbamazepine, improved following the blind addition of lithium. The clinical and theoretical implications of the response to this combination treatment are discussed.