Hydrosoluble diclofenac epolamine (DHEP) represents an interesting approach to acute migraine attacks, where gastrointestinal motility and drug absorption are often reduced. Its efficacy was investigated in a randomized, crossover, double-blind trial on 155 patients who treated four consecutive mild-to-moderate migraine attacks, either with DHEP (65-mg sachet) or placebo. If pain was not relieved within 1 h, a second dose was given. The total number of treated attacks was 481. A pain-free condition was achieved within 2 h in 45.8% and 25.1% of attacks treated, respectively, with DHEP or placebo (P < 0.0001), with a therapeutic gain of 20.7%. Time to attack resolution, light and noise sensitivity and impact on working ability were significantly reduced by DHEP compared with placebo. Moreover, significantly fewer patients required a second drug dose or a rescue medication when treated with DHEP than with placebo. No adverse reaction was recorded. In conclusion, DHEP was effective and safe for pain relief in patients with an acute mild-to-moderate migraine attack.