Background/Purpose: To compare the efficacy and safety profile between intramuscular (IM) olanzapine and IM haloperidol plus IM lorazepam in acute schizophrenic patients with moderate to severe agitation. Methods: This was a prospective, randomized, open-label study. Acutely agitated patients with schizophrenia or schizoaffective disorder (. n=67) were randomized to receive 10mg IM olanzapine (. n=37) or 5mg IM haloperidol plus 2mg IM lorazepam (. n=30). Agitation was measured with Positive and Negative Syndrome Scale Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES) during the first 2 hours and at 24 hours after the first injection. Safety was assessed using the Simpson-Angus Scale and Barnes Akathisia Rating Scale and by recording adverse events at 24 hours following the first injection. The Clinical Global Impression-Severity scale was also rated. Results: The PANSS-EC scores decreased significantly at 2 hours after the first injection in both groups (olanzapine: -10.2, p<0.001; haloperidol+lorazepam: -9.9, p<0.001). Haloperidol plus lorazepam was not inferior to olanzapine in reducing agitation at 2 hours. There were no significant differences in PANSS-EC or ACES scores between the two groups within 2 hours following the first injection. The frequencies of adverse events and changes in Clinical Global Impression-Severity, Simpson-Angus Scale, and Barnes Akathisia Rating Scale scores from baseline to 24 hours showed no significant differences between the groups. Conclusion: The findings suggest that IM haloperidol (5mg) plus lorazepam (2mg) is not inferior to IM olanzapine (10mg) in the treatment of acute schizophrenic patients with moderate to severe agitation (. ClinialTrials.gov identifier number NCT00797277).