Mixed mania (i.e., a manic syndrome accompanied by depressive symptoms) and its response to long-term preventive drug treatment was studied as part of a larger NIMH collaborative study. Following recovery from a manic episode, patients received either lithium, imipramine, or the combination of lithium and imipramine for a 2-year period. It was found that patients who had recovered from a mixed manic state were at significantly higher risk for recurrences than patients who had recovered from a pure (non-mixed) manic state. Lithium and the combination of lithium and imipramine were highly effective preventive treatments for the pure manic group and poor treatments for the mixed group. Imipramine was ineffective for both the pure and mixed groups. The need for identifying mixed mania in therapeutic trials and in evaluating alternative treatments for lithium with this subgroup is discussed.