Zolmitriptan is a 5-HT1B/1D receptor agonist for the acute treatment of migraine. This study examined the efficacy of a second dose of zolmitriptan for the treatment of persistent or recurrent headache. Part 1 was a randomised, placebo-controlled, double-blind evaluation of 2.5 mg and 5 mg zolmitriptan for the treatment of persistent migraine headache, two hours after an initial dose of 2.5 mg zolmitriptan. In part 2 (open-label), patients treated the first two attacks with 2.5 mg zolmitriptan, thereafter patients could treat any initial, persistent or recurrent migraine headache with 2.5 mg or 5 mg zolmitriptan. The unique design of this trial allowed patients to adjust their treatment to attain maximum headache relief and control of their disease. Of 2800 patients treating an initial migraine headache in Part 1, 989 patients took a second dose to treat persistent headache of moderate or severe intensity. Headache response rates were similar across the three treatment groups, but the pain-free response rate was significantly higher with 5 mg zolmitriptan than with placebo (p < 0.001). In Part 2, 2499 patients treated 49,784 migraine attacks (excluding the first two attacks, which had to be treated with 2.5 mg zolmitriptan), of which 66% required only a single dose of zolmitriptan. Patients treated 22% of attacks with a second dose of zolmitriptan for persistent headache. A headache response was achieved in 80% and 73% of persistent headaches treated with 2.5 mg or 5 mg zolmitriptan, respectively. Corresponding pain-free responses following treatment of persistent headaches of any intensity were 64% and 52%. Eight per cent of attacks were treated with a second dose of zolmitriptan for moderate or severe recurrent headache. A headache response was achieved in 90% and 86% of moderate/severe attacks, with a pain-free response in 78% and 70% of attacks of any intensity treated with 2.5 mg and 5 mg, respectively. Zolmitriptan was well tolerated. In conclusion, 2.5 mg and 5 mg zolmitriptan are highly effective in treating both persistent and recurrent migraine headache.