Forty female and 16 male adult migraineurs were subjects in a double-blind, three-way crossover trial to compare the effectiveness and safety of isometheptene mucate, acetaminophen, and dichloralphenazone combination (Midrin) with that of acetaminophen alone and of placebo. Forty-three patients had common migraine and 13 had classic migraine. Each subject and the investigator evaluated the effectiveness of medication in 6 headache episodes (two replications of each test medication); subjects also rated peak headache severity for each of the six episodes. For subjects' evaluations of relief and headache severity and investigator's assessments of relief, the isometheptene combination proved superior (P<0.05). The least number of capsules was taken during episodes for which the isometheptene combination was the test medication. Other known headache medications were also taken least during isometheptene combination tests. This suggests greater effectiveness of isometheptene combination therapy. Nausea and vomiting occurred in association with ten isometheptene combination, 7 acetaminophen and 18 placebo episodes. Other untoward effects of test meditation were mild and reversible and were also frequently associated with placebo medication.