Migraine is much more common in women (18%) than in men (6%). Menstrual migraine in female migraineurs also varies from 7 to 19%. The main goals of the present study were (1) to investigate gender specific differences in an experimental capsaicin model of trigeminal sensitization (a proposed mechanism of migraine) and (2) to explore the influence of menstrual cycle phases. Twenty-eight healthy female and male volunteers were studied. Capsaicin (100 microg/0.1 ml) was injected intradermally to the forehead. Pain intensity and distribution together with the visual flare and allodynic area (central sensitization) were assessed for females (during their menstrual and luteal phases) and for males. Pain area significantly changed across the menstrual cycle with 19.2+/-2.0 cm x min at menstrual and 16.4+/-0.9 cm x min at luteal phase (P<0.001). The area was significantly larger in both phases for females compared to males (14.2+/-1.3 cm x min, P<0.0001). Flare area at menstrual phase (69.2+/-4.2 cm(2)) was significantly (P<0.0001) larger than luteal phase (58.6+/-2.1 cm(2)). Females, in both phases, showed larger flare area compared to males (44.9+/-3.6 cm(2), P<0.0001). Area of brush-evoked allodynia was also larger at the menstrual phase compared to the luteal phase (P<0.0001) and males (P<0.0001). A significant difference was found in the capsaicin-evoked pain distribution with a greater response in menstrual phase compared to the luteal phase (P<0.01) and men (P<0.0001). Capsaicin induced trigeminal sensitization and evoked gender specific sensory and vaso-motor responses, with menstruating females generally showing the strongest manifestations. The model may be further applied to explore mechanisms of human trigeminal sensitization.