We have previously shown that nitric oxide (NO) and cyclic guanosine monophosphate (GMP) may cause headache and migraine. However, not all findings in previous studies can be explained by an activation of the NO-cGMP pathway. Calcitonin gene-related peptide (CGRP) causes headache and migraine in migraine patients, but CGRP receptor activation causes an increase in cyclic adenosine monophosphate (cAMP). In order to investigate the role of cAMP in vascular headache pathogenesis, we studied the effect of cilostazol, an inhibitor of cAMP degradation, in our human experimental headache model. Twelve healthy volunteers were included in a double-blind, randomized, crossover study. Placebo or cilostazol (200 mg p.o.) was administered on two separate study days. Headache was scored on a verbal rating scale (0-10) and mechanical pain thresholds were measured with von Frey hairs. The median peak headache score 0-16 h postdose was 0 (range 0-2) after placebo and 3.5 (range 0-7) after cilostazol (P = 0.003). The median headache curve peaked at 6-9 h postdose. The headaches induced were usually bilateral and pulsating. Nausea occurred in two volunteers, photo- and phonophobia were not seen. Two volunteers had a headache that fulfilled International Headache Society criteria for migraine without aura after cilostazol. No change in mechanical pain thresholds in the forehead was seen (P = 0.25). The headache after cilostazol was equal to or more severe than headache induced by glyceryl trinitrate in previous experiments. The present study thus indicates that increased levels of cAMP may play a role in headache and migraine pathogenesis.