Rapid control of agitation is of critical importance in the treatment of acutely ill patients with schizophrenia. Both olanzapine and aripiprazole have been shown to be safe and effective in this setting, with each having somewhat different receptor binding affinity profiles. This 5-day, randomized, double-blind trial evaluated relative improvements in agitation in hospitalized patients who received orally dosed olanzapine (n = 306, 20 mg/d) or aripiprazole (n = 298, 15 mg/d, increasing to 30 mg/d as needed). Lorazepam was also given as needed (total dose, ≤4 mg/d) but not in place of a study drug dose increase. The primary efficacy measure was daily mean change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score. Secondary measures of positive symptoms and safety were also assessed. Significant improvements from baseline in PANSS-EC and secondary efficacy measures were seen for both olanzapine and aripiprazole (P < 0.001),with no between-group differences. A greater proportion of aripiprazole-treated patients received lorazepam at each visit compared with olanzapine-treated patients, but this difference was significant only at visit 5 (41.2% vs 31.0%, P = 0.033). Fasting glucose and triglycerides increased more significantly in olanzapine-treated patients (P = 0.030 and P < 0.001, respectively). Prolactin increased in the olanzapine group and decreased in the aripiprazole group with a significant between-group difference (P < 0.001). During the first 5 days of randomized treatment, olanzapine and aripiprazole displayed similar efficacy profiles for treating agitation associated with schizophrenia. Aripiprazole-treated patients had smaller increases in glucose and lipids, but no difference was observed between treatments in the proportion of patients experiencing categorical shifts in these measures.