Cyclandelate inhibits calcium-induced contraction of vascular smooth muscle cells, platelet aggregation induced by thrombin, platelet-activating-factor and adenosine, and also suppresses a provoked 5HT release from platelets. This pharmacological profile suggests that cyclandelate may have a potential prophylactic effect in migraine. To test this hypothesis, a double-blind multicentre study was performed in 214 patients to investigate the efficacy and tolerability of cyclandelate compared to placebo and propranolol. After a 4-week baseline period, eligible patients (randomization 3:2:3) were treated for 12 weeks with daily doses of 1.200 mg cyclandelate (n=81), placebo (n=55) or 120 mg propranolol (n=78). The number of migraine attacks (350% responders) and the migraine duration/month were compared based on the difference between baseline and the last 4 weeks of prophylactic treatment. The percentage of patients with a reduction in migraine attacks of 350% treated with cyclancelate (37.0%) or propranolol (42.3%) was not significantly superior to placebo (30.9%; P>0.025). The mean duration of migraine in hours (h) per month decreased in both active treatment groups (cyclandelate: 36.8h, p=0.046; propranolol: 34.4 h, p=0.039) compared to placebo (13.7 h) without reaching statistical significance (alpha/2=0.025). The clinical efficacy of cyclandelate and propranolol was comparable. Adverse experiences were reported by 13 patients (16.0%) treated with cyclandelate, by 5 patients (9.1%) treated with placebo and by 19 patients (24.4%) treated with propranolol. These were drug-related in 7.1% (n=6) of patients treated with cyclandelate and in 9% (n=7) of patients treated with propranolol. In summary, cyclandelate has a comparable efficacy to that of propranolol an established drug of first choice in the prophylaxis of migraine. Both drugs were better than placebo, but not significantly so. Both active treatments were well tolerated.