Objective: To examine the benefits of acetaminophen, aspirin, and caffeine (AAC) in the treatment of severe, disabling migraine attacks, in a population of migraine sufferers for whom over-the-counter (OTC) medications are appropriate. Background: Subjects (n=1220) who met the International Headache Society criteria for migraine with or without aura were included in three independent clinical studies. Design/Methods: Post-hoc analysis of 172 subjects who met the criteria for severe, disabling migraine reported a history of migraine attacks characterized by at least severe pain and severe disability, and treated attacks with severe pain and at least severe disability. Subjects who usually vomited with 20% or more of their migraine attacks, and those with incapacitating disability (subjects who required bed rest for more than 50% of their attacks) were not eligible for enrollment. Results: From 1 h and continuing through 6 h postdose, the proportion of responders was significantly greater (p≤0.01) for AAC than placebo. The pain intensity difference from baseline was significantly greater (p≤0.05) for AAC than placebo from 0.5 h through 6 h. The proportion of subjects reporting improvement in functional disability, photophobia, and phonophobia was significantly greater for AAC than placebo from 2 h through 6 h postdose. Conclusions: The nonprescription combination of AAC was well tolerated and effective.