The aim of this study was to determine the characteristics of placebo effects in acute migraine treatment trials of triptans performed over 12 years and assess whether the use of placebo controls in trials of acute migraine treatment remains ethically and scientifically appropriate. We conducted a search for all controlled trials published in English between January 1991 and April 2002 in which adult subjects with migraine were randomly assigned to receive an oral triptan or placebo for the acute treatment of a migraine attack. Thirty-one trials met our criteria for inclusion. Placebo results for each study and pooled placebo results were calculated for the endpoints of headache response, pain-free response and adverse events. Heterogeneity was assessed using the Q statistic, and meta-regression using prespecified covariates was performed to investigate heterogeneity. The study results show a significant degree of heterogeneity. Efforts to explain heterogeneity with available data were not successful, with the exception of adverse event rates to placebo, for which study location (Europe vs. North America) partially explained differences in study results. AE rates were lower in European studies than in North American studies. Across all studies, the mean proportion of subjects who experienced a treatment response at two hours to placebo was 28.48 +/- 8.73% (range 17-50%). The mean proportion of subjects who experienced an adverse event to placebo was 23.40 +/- 14.05% (range 4.86-74%). The mean proportion of subjects who experienced a pain-free response to placebo at two hours was 6.08 +/- 4.43% (range 5-17%). Results of studies allowing use of prophylaxis did not differ significantly from those that did not allow prophylaxis. Placebo effects appear to be enhanced in studies involving children and adolescents. In contrast to an earlier, smaller review, our results do not suggest that randomization ratios influence placebo rates. We conclude that placebo effects in published trials of acute migraine medications are highly variable and often substantial. This variability in placebo response means that active control equivalence trials or the use of historical controls will not provide adequate proof of the safety or efficacy of new drugs, and will not differentiate between drugs that are active vs. placebo but of unknown efficacy relative to each other. The potential for approval of ineffective drugs, inability to compare results of studies performed in different locations, and poor characterization of the tolerability and safety profiles of new drugs represent a greater danger to migraineurs than does the limited-duration use of placebo in carefully monitored clinical trials of consenting subjects. These observations support the view that the inclusion of a placebo group remains of major scientific and ethical importance in trials of migraine medications.