We tested the hypothesis that the presence of unilateral cranial autonomic symptoms in migraine predicts a good response to triptans. In this randomized, double-blind, placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to rizatriptan 10 mg wafer or placebo (ratio 1:1) and treated for a single moderate or severe migraine attack. The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h. Secondary endpoints included pain relief, no associated symptoms and sustained pain freedom or relief. Significantly more patients reported pain freedom at 2 h after taking rizatriptan than after placebo (54% vs 8%; p<0.001). Similarly, significantly more patients reported total migraine freedom at 2 h after rizatriptan than after placebo (51% vs 8%; p<0.001). Rizatriptan was also more effective than placebo on most secondary endpoints. Migraineurs with unilateral cranial autonomic symptoms respond better than the general migraine population to rizatriptan, probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular 5-HT1B/1D receptors. Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients.