In case reports of patients with bipolar disorder, atypical antipsychotic drugs are often associated with an exacerbation of manic symptoms. To determine whether the atypical antipsychotic drug ziprasidone is associated with an exacerbation of manic symptoms or a worsening of depressive symptoms when used to treat bipolar mania, we analyzed data pooled from 2 similarly designed randomized, placebo-controlled trials of ziprasidone monotherapy in the treatment of bipolar mania (ziprasidone: n=268, placebo: n=131). Exacerbation of mania was defined as CGI-S ≥ 5 and HAM-D increase from baseline to endpoint ≤ 25%, and worsening of depression was defined as HAM-D at endpoint ≥ 15 and HAM-D change from baseline to endpoint ≥ 20%. A significantly smaller proportion of subjects experienced an exacerbation of mania in the ziprasidone group than in the placebo group (6.7% vs 17.6%, P < 0.001). An analysis of dysphoric/nondysphoric and psychotic/nonpsychotic subpopulations showed significantly smaller proportions of ziprasidone subjects with an exacerbation of mania than placebo subjects in all 4 subsets (P < 0.05). The proportion of subjects experiencing a worsening of depression was smaller in the ziprasidone group than in the placebo group (1.9% vs 4.6%, n.s.). These results strongly suggest that ziprasidone causes neither exacerbation of mania nor worsening of depression in patients with acute bipolar mania. Future research will address this issue in patients with bipolar depression.