Dysphoric mania is a common and often difficult-to-treat subset of bipolar mania that is associated with significant depressive symptoms. In addition to improving mania, ziprasidone has been found to reduce HAM-D scores in subjects with mixed mania. This post-hoc analysis evaluated the efficacy of ziprasidone in the treatment of depressive and other symptoms in patients with dysphoric mania. Pooled data were examined from 2 similarly designed, 3-week, placebo-controlled trials in acute bipolar mania. Subjects were considered to have dysphoric mania if they scored ≥ 2 on at least 2 items of the extracted HAM-D scale (dysphoric mood, worry, self-reproach, and negative self-evaluation). Changes in HAM-D scores from baseline to Days 2, 4, 7, 14, and 21 were evaluated by a mixed-model analysis of variance. Additional assessments included changes in the MRS, CGI-S, PANSS, and GAF scores. Starting on Day 4, HAM-D scores were significantly lower at all visits in subjects treated with ziprasidone compared with those treated with placebo (P < 0.05). Mean (± SD) improvement in HAM-D score in subjects treated with ziprasidone at study endpoint was –4.2 ± 0.7), a reduction of 44% from baseline. Ziprasidone-treated subjects also demonstrated significant and persistent improvements on the MRS, CGI-S, PANSS, and GAF scores compared with placebo, starting at Days 2, 2, 7, and 7, respectively. In conclusion, in placebo-controlled trials, ziprasidone significantly improved depressive and other symptoms associated with dysphoric mania.