Caffeine consumption may cause headache, particularly migraine. Its withdrawal also produces headaches and may be related to weekend migraine attacks. Transcranial Doppler sonography (TCD) has shown changes in cerebral blood flow velocities (BFV) during and between attacks of migraine. In order to examine whether headache and changes in BFV could develop from controlled caffeine alterations, 20 healthy volunteers without a headache history, underwent clinical evaluation, TCD and serum caffeine measurements on four occasions, comparing conditions of regular caffeine intake, caffeine withdrawal and "re-caffeination". After 24 h of complete caffeine abstinence, 10 suffered from moderate to severe headaches with complete recovery within 1 h after caffeine intake. The BFVs in both middle cerebral, both posterior cerebral and basilar arteries were higher following the withdrawal period, reaching statistical significance in the left middle cerebral basilar and both posterior cerebral arteries. BFVs decreased significantly within half an hour after caffeine intake in all subjects, and were similar to baseline values after 2 h. Our results emphasize the relationship between caffeine withdrawal, the development of headache and alterations in cerebral blood flow velocities. Also, these findings indicate that accurate interpretation of TCD measurements should account for the influence of caffeine on BFVs.