Background and Purpose–Factor V Leiden and a prothrombin gene variant, G20210A, are mutations associated with a thrombotic risk. The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age. Methods–We conducted a case-control study in western Washington state. Case patients were women aged 18 to 44 years with a first stroke (n=106). Control subjects were women without stroke recruited from the same region by use of random-digit telephone dialing (n=391). All were interviewed and provided blood specimens, which were genotyped for these mutations. Results–Factor V Leiden was found in 0.9% of case patients, a single patient with a subarachnoid hemorrhage, and in 4.1% of control subjects. The odds ratio (OR) for any stroke was 0.2 (95% confidence interval [CI], 0.03 to 1.7). The prothrombin variant was found in 1.9% of case patients, 1 with a venous stroke and 1 with an ischemic stroke, and in 1.6% of control subjects. The OR for any stroke was 1.48 (95% CI, 0.14 to 9.17). ORs for stroke types were also not statistically significant. Conclusions–In this study, neither factor V Leiden nor the prothrombin variant (G20210A) was an important risk factor for stroke in young women. In this setting, screening for these mutations cannot be recommended. Unanswered by this study is whether screening would be useful in select patients, such as those with a strong family history of thrombophilia or those with venous strokes.