Background: This randomized controlled trial compares the efficacy and safety of olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania. Methods: The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of olanzapine (5-20 mg/d, n = 234) with haloperidol (3-15 mg/d, n=219). Results: Rates of remission (Young-Mania Rating Scale score of ≤12 and 21-item Hamilton Rating Scale for Depression score of ≤8 at week 6) were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P=.15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P=.04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated patients, respectively (P=.56). Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques (P=.04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group. Conclusions: These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain.