OBJECTIVE: To compare the clinical and health-related quality of life outcomes associated with olanzapine and haloperidol treatment in patients with bipolar disorder. METHODS: Patients (N = 453) with bipolar I disorder (manic or mixed episode) were randomized to either olanzapine 5-20 mg/day or haloperidol 3-15 mg/day for 12 weeks. The primary clinical outcome was the symptomatic remission rates, as defined a priori by the proportion of patients having a Y-MRS total score ??12 and a HAMD-21 total score ??8, at 6 weeks and 12 weeks. The humanistic outcomes were measured as changes from baseline to endpoint (week 6 or week 12) in the scores of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). RESULTS: Olanzapine-treated patients had a higher remission rate than haloperidol at six weeks (52% versus 46% p = .15) and at 12 weeks (52% versus 44%, p = .08). At week six, significant changes in 5 SF-36 domains of general health (p = .010), physical functioning (p < .001), role limitations due to physical health problems (p < .001), social functioning (p < .05), and vitality (p < .01), were found in favor of olanzapine-treated patients as compared to haloperidol. At week 12, olanzapine treatment maintained the significantly favorable changes in the same domains with the exception of social functioning. None of the SF-36 domains was in favor of haloperidol at week 6 or week 12. CONCLUSIONS: Compared to haloperidol, olanzapine treatment was associated with the improvements in the clinical and health-related quality of life outcomes in patients with bipolar disorder. STATEMENT OF SIGNIFICANCE: Compared to haloperidol, olanzapine treatment was associated with the improvements in the clinical and health-related quality of life outcomes in patients with bipolar disorder.