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Background: Scarce information is available on the usefulness of new prediction markers for identifying young ischemic stroke patients at highest risk of recurrence. Methods: The predictive effect of traditional risk factors as well as of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, and the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene on the risk of recurrence was investigated in a hospital-based cohort study of 511 ischemic stroke patients younger than 45 years followed up for a mean of 43.4 months. Outcome measures were fatal/nonfatal myocardial infarction, ischemic stroke, or TIA. Risk prediction was assessed with the use of the concordance c ( c index), and the Net Reclassification Improvement (NRI). Results: The risk of recurrence increased with increasing number of traditional factors (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.57–3.35 for subjects with 1 factor: HR 5.25, 95% CI 2.45–11.2 for subjects with 2), as well as with that of predisposing genotypes (HR 1.96, 95% CI 1.33–2.89 for subjects carrying 1 at-risk genotype; HR 3.83, 95% CI 1.76–8.34 for those carrying 2). The c statistics increased significantly when the genotypes were included into a model with traditional risk factors (0.696 vs 0.635, test z = 2.41). The NRI was also significant (NRI = 0.172, test z = 2.17). Conclusions: Addition of common genetic variants to traditional risk factors may be an effective method for discriminating young stroke patients at different risk of future ischemic events.