BACKGROUND Standard treatment for acute psychotic agitation often involves intramuscular administration of the benzodiazepine lorazepam and the antipsychotic haloperidol. This study compared the efficacy and safety of oral treatment with the atypical antipsychotic risperidone plus lorazepam with those of standard intramuscular treatment. We hypothesized that the efficacy and speed of action of both treatments would be similar. METHODS In a prospective, parallel-group, randomized, rater-blinded noninferiority study conducted at 24 sites in the United States, 162 patients exhibiting agitation associated with active psychosis were randomly assigned to receive either oral treatment with 2 mg of risperidone plus 2 mg of lorazepam (N = 83) or intramuscular treatment with 5 mg of haloperidol plus 2 mg of lorazepam (N = 79). The change scores on a 5-item acute-agitation cluster from the Positive and Negative Syndrome Scale (hallucinatory behavior, excitement, hostility, uncooperativeness, and poor impulse control) were the main outcome measure. The study was conducted from January 8 to August 8, 2001. RESULTS Mean acute-agitation cluster scores were similar in the 2 groups at baseline. Mean score improvements at 30, 60, and 120 minutes after dosing were significant at each timepoint in both groups (p <.0001) and were similar in both groups (p >.05). Both treatments were well tolerated. CONCLUSIONS A single oral dose of risperidone plus lorazepam was as effective as parenterally administered haloperidol plus lorazepam for the rapid control of agitation and psychosis. These findings suggest that this oral regimen is an acceptable alternative to the current intramuscular treatment for acute psychotic agitation.