We assessed whether heterozygosity for the thrombophilic Leiden mutation of the factor V gene (MFV) was pathogenetic for alveolar osteonecrosis of the jaw and chronic facial pain (neuralgia-inducing cavitational osteonecrosis (NICO)) in 89 patients with NICO. A second specific aim was to assess for thrombophilic synergism between exogenous estrogens and MFV for development of osteonecrosis of the jaw. MFV was found in 24% of the patients, 16 (21%) of 76 women and 5 (39%) of 13 men. The mutation was much less common in healthy normal controls: 3 (3%) of 101 women (chi2 = 14.8, p = 0.001) and 4 (3.7%) of 108 men (chi2 = 20.4, p = 0.001). Patients with and without MFV did not differ in tissue plasminogen activator activity, plasminogen activator inhibitor activity, proteins C and S, lipoprotein (a), or anticardiolipin antibodies (p > 0.05). Use of standard-dose oral contraceptives and/or postmenopausal estrogens before the development of NICO was more common in female patients with MFV (13 (81%) of 16) than in those without it (23 (38%) of 60; chi2 = 9.33, p = 0.002). When the thrombophilic effects of such exogenous estrogens were superimposed on the familial resistance to activated protein C associated with MFV, thrombophilia was augmented and the risk of osteonecrosis was increased. Since heterozygosity for this mutation occurs in at least 3% of unselected, healthy women, measurement of resistance to activated protein C and MFV would identify women at high risk for venous thrombosis and osteonecrosis, in whom use of oral contraceptives or postmenopausal estrogens might be contraindicated, while identifying a much larger group of women (approximately 97%) without the mutation whose risk from exogenous estrogens would be low.