(Headache 2009;49:1324-1332) Objective and Background.— Ranges of agents are used in the emergency departments to treat migraine headache. Some experts suggest that phenothiazines are among the most effective; clinical trials have been small with varied results. We performed a systematic review and meta-analysis to determine the relative effectiveness of phenothiazines compared with placebo and other active agents for the treatment of acute migraine. Methods.— We searched MEDLINE, EMBASE, CINAHL, Cochrane database, and international clinical trial registers for randomized controlled trials comparing parenteral phenothiazines with placebo or another active parenteral agent for treatment of acute migraine in adults. The primary outcome was relief of headache, and secondary outcome was clinical success. Analysis was for phenothiazines vs placebo, pooled other active agents, and metoclopramide for each outcome. Odds ratios (ORs) were calculated and pooled by using a random effects model (RevMan v5). Results.— Thirteen trials were appropriate and had available data. Phenothiazines were compared with placebo in 5 trials and to another active agent in 10 (metoclopramide 4). Phenothiazine was more effective than placebo for headache relief (OR 15.02, 95% confidence interval [CI] 7.57-29.82) and clinical success (OR 8.92, 95% CI 4.08-19.51). Phenothiazines were more effective than other agents combined (OR 2.04, 95% CI 1.25-3.31) and the metoclopramide subgroup (OR 2.25, 95% CI 1.29-3.92) for clinical success, but no differences were found for headache relief. The clinical success rate of phenothiazines was 78% (95% CI 74-82). Conclusion.— Phenothiazines are more effective than placebo for the treatment of migraine headache and have higher rates of clinical success than other agents against which they have been compared.