Methodological aspects of study design affect therapeutic outcome. We tested the hypothesis that treatment effect of an active drug in studies on acute therapy of migraine is lower in placebo-controlled studies than in those not using a placebo-controlled design. From 522 eligible studies on acute therapy of migraine cited in Pubmed database which were published between 1964 and 1997 we randomly selected 100 studies for evaluation. We excluded five studies because they did not include a quantitative measurement of pain intensity. Of the 95 studies included in the analysis, 61 used placebo control. Response to active drug was significantly lower (P < 0.05) in placebo-controlled studies (61% [lower and upper quartiles 44% and 75%] vs. 71% [56% and 75%]). We did not find any significant effect of quality of study design on net effect of verum. This observation should be taken into account for future planning of controlled clinical studies in acute migraine.