We hypothesized that there was a pathophysiologic association between coagulation disorders, polycystic ovary syndrome (PCOS) and idiopathic intracranial hypertension (IIH). Thrombophilic hyperestrogenemia of pregnancy, exogenous estrogens, obesity, and hypofibrinolysis of PCOS have been associated with IIH. Polymerase chain reaction (PCR) and serologic coagulation measures were done in 65 women (64 white) with IIH, PCR in 102 healthy white female controls (72 children, 30 age-matched adults), and serologic measures in the 30 adults. Of the 65 cases, 37 (57%) were found to have PCOS, 16 of whom (43%) were obese (BMI $ 30-40), and 19 (51%) extremely obese (BMI $ 40). Of the 65 women with IIH, 25 (38%) were homozygous for the thrombophilic C677T MTHFR mutation vs. 14% (14/102) controls (p = .0002). Thrombophilic high (> 150%) Factor VIII was present in 9/65 (14%) IIH cases vs. 0/30 (0%) controls, Fisher's p = .053. Elevated lipoprotein (a) ($ 35 mg/dL), associated with hypofibrinolysis, was present in 19/65 (29%) IIH cases vs. 3/30 (10%) controls, p = .039. IIH occurred on estrogen-progestin contraceptives in 18/65 IIH cases (28%), on hormone replacement therapy in 6 (9%), and during pregnancy in 5 (8%). We speculate that PCOS, associated with obesity and extreme obesity, is a treatable promoter of IIH. If thrombophilia-hypofibrinolysis and subsequent thrombosis are associated with reduced CSF resorption in the arachnoid villi of the brain, we speculate that thrombophilia-hypofibrinolysis, often augmented by thrombophilic exogenous estrogens, pregnancy, or the paradoxical hyperestrogenemia of PCOS, are treatable promoters of IIH.