In order to evaluate a possible association between migraine and restless legs syndrome (RLS), we performed a case-control study on the comorbidity of RLS and migraine. Patients with migraine (n = 411) and 411 sex- and age-matched control subjects were included. Migraine was diagnosed according to International Headache Society criteria, RLS according to the criteria of the International Restless Legs Syndrome Study Group. Furthermore, all patients had to fill out a self-assessment test performance on depression [Beck's Depression Inventory (BDI)]. RLS frequency was significantly higher in migraine patients than in control subjects (17.3% vs. 5.6%, P < 0.001; odds ratio 3.5, confidence interval 2.2, 5.8). In our sample, there was no significant association between migraine and depression as defined by the BDI score (9.6% in migraine vs. 4.0% in control subjects, P = 0.190). Depression was, however, not significantly more frequent in migraine patients with RLS (13.6%) than in migraine patients without RLS (8.7%). In addition, migraine patients with RLS had a significantly higher BDI score. RLS features did not differ significantly between migraine patients with RLS and control subjects with RLS. There is an association between RLS and migraine and, in addition, a co-association with depression. The underlying mechanism, however, remains undetermined and might be related to a dysfunction of dopaminergic metabolism in migraine.