Dopamine D(2) antagonists are known to induce akathisia, the emergency management of which remains undetermined. We sought to evaluate the effectiveness of diphenhydramine in the treatment of akathisia induced by 10 mg intravenous prochlorperazine. This prospective, open-label, uncontrolled study evaluated a cohort of akathisic adult Emergency Department patients who were participating in a series of three studies of acute akathisia at an academic medical center. Each subject received intravenous diphenhydramine, with akathisia measurements (graded from 0-17 points) performed just before and 30 min after infusion. Mean scores were calculated using descriptive statistical analyses. The effect of treatment was evaluated using the paired t-test. For the 87 akathisic patients, the mean score before treatment was 9.8 +/- 3.6, and after treatment was 1.2 +/- 2.6, a mean reduction of 8.5 +/- 3.8 (95% confidence interval [CI], 7.8 to 9.4; p < 0.0001). In conclusion, intravenous diphenhydramine rapidly reduces signs and symptoms of acute akathisia induced by prochlorperazine.