BACKGROUND Recurrent pregnancy loss may result from hypercoagulability. OBJECTIVE To determine whether women with factor V Leiden mutation, a common inherited defect of coagulation, are at increased risk for recurrent pregnancy loss. DESIGN Case-control study. SETTING University hospital. PATIENTS 113 consecutive women referred for evaluation of recurrent spontaneous abortion (case-patients) and 437 postmenopausal women with at least one successful pregnancy and no history of pregnancy loss (controls). An additional survey of 387 postmenopausal women with at least one pregnancy loss was also conducted. MEASUREMENTS Prevalence of factor V Leiden mutation determined by a second-generation screening test for resistance to activated protein C with genetic confirmation of all borderline and low-value results. RESULTS Prevalence of the factor V Leiden mutation was greater among case-patients (8.0%) than among controls (3.7%) (odds ratio, 2.3 [95% CI, 1.0 to 5.2]; P = 0.050). In the subgroup of case-patients with three or more pregnancy losses and no successful pregnancies, prevalence of the mutation was 9.0% (odds ratio, 2.6 [CI, 1.0 to 6.7]; P = 0.048). Among the additional women surveyed, the prevalence of the mutation in those with three or more pregnancy losses (7.5%) was almost identical to that in case-patients. Thus, in all evaluated women with several pregnancy losses, the prevalence of factor V Leiden was increased 2.2-fold (P = 0.026). CONCLUSION These data are compatible with the hypothesis that factor V Leiden mutation may play a role in some cases of unexplained recurrent pregnancy loss.