A nasal spray preparation of salmon calcitonin (sCT) was administered to migrainous patients to evaluate the activity of sCT in migraine, and to better define its pharmacological profile. Twenty-two patients with common migraine (CM) concluded a double-blind, parallel trial versus placebo. A 30-dayrun-in period preceded a 3-month period of therapy with sCT (200 UI at bed time), or with placebo. SCT was able to significantly reduce Headache Index, Pain Total Index (PTI) and analgesic consumption, from the first month of therapy. Another 10 patients suffering from migraine with interval headache (MIH) were admitted to an open study: a 10-day run-in period preceded a 30-day phase of sCT (200 UI at bed time) administration. SCT induced a significant PTI reduction during the last 10-days of treatment, while analgesic consumption improved significantly in the first ten days. Nociceptive flexion reflex threshold and plasma levels of β-endorphin and β-lipotropin, evaluated at the end of the run-in and treatment periods to assess patients' antinociceptive state, did not change significantly. Our results demonstrate the effectiveness of sCT nasal spray preparation in treating migraine, and suggest a peculiar and complex pharmacological profile for sCT ranging from analgesic activity to modulation of the neuronal and neuro-transmitter process subserving migraine attacks.