To investigate whether the novel, potent and highly selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist ICS 205-930 can prevent migraine attacks, we conducted simultaneously two randomized, double-blind, placebo-controlled, multicentre, international trials, involving a total of 204 patients, suffering from classic or common migraine. Both trials had the same parallel-group design (1 month baseline observation, followed by 3 months treatment) and both produced remarkably similar results. The primary efficacy parameter was the proportional reduction in attack frequency recorded after 3 months of treatment. Twenty-two patients withdrew prematurely from the trials and could not be assessed for efficacy. Mild to severe constipation was reported by about 50% of the patients on active treatment. None of the doses of ICS 205-930 tested (50 mg, 25 mg and 15 mg daily) produced a statistically significantly better result to reduce attack frequency than did placebo. However, confidence intervals for the difference in effect with placebo were wide, indicating that 15 mg ICS 205-930 may produce a 57% reduction in attack frequency as compared to placebo. The most unusual finding was that, for all efficacy parameters, the best results were obtained with the lowest dose (15 mg), the worst results with the highest dose (50 mg) and an intermediate effect with 25 mg. Such an inverse relation between dose and efficacy suggests a bell-shaped dose-response curve, implying that doses lower than 15 mg might well prove to be more effective. Thus, the present study has produced inconclusive, but intriguing results. Lower doses should be further investigated before drawing any definite conclusion on the efficacy of ICS 205-930 in the prophylactic treatment of migraine.