At a young age, ischemic stroke is an uncommon event in which prothrombotic factors are likely to play an important role. In 202 referred cases, 105 men and 97 women, median age 39 years (range, 3 to 50), with a history of ischemic stroke and in 1036 age frequency-matched apparently healthy individuals from the same ethnic background, we have investigated whether inherited prothrombotic conditions increase the risk of ischemic stroke. Neither abnormal plasma levels of natural anticoagulants and fibrinogen nor significant increase of the prothrombin A20210 allele was found in stroke cases compared with controls. Hypertension (odds ratio [OR], 22.61), male sex (OR, 2.30), smoking (OR, 2.78) and alcohol habits (OR, 0.14), a personal history of venous thromboembolism (OR, 4.53), a family history of stroke (OR, 1.93), high circulating levels of fibrinogen (P=0.0190), and total cholesterol (P=0.101) were all independently associated with ischemic stroke. Compared with noncarriers, carriers of the factor V (FV) Leiden mutation (OR, 2.56), and to a lesser extent, of the methylenetetrahydrofolate reductase (MTHFR) TT genotype (OR, 1.60), had an independent higher estimated risk of having a history of ischemic stroke. The relationship with the FV Leiden mutation was greater in women (OR, 3.95). Thus, in addition to established determinants, FV Leiden mutation is independently associated with the occurrence of ischemic stroke in this setting. The greater association in women suggests the possibility of an interaction of this genotype with female hormones.