The aim of the study is to determine if a novel thrombophilia mechanism (factor V Leiden) that is associated with resistance to activated protein C (APC) is in itself a risk factor for the development of ischemic stroke (IS). Sixty-six controls and 66 patients with IS were included in an unmatched case-control study. In the group of patients selected for this study, other causes of IS were ruled out. APC resistance was considered if activated partial thromboplastin time (aPTT) measured in the presence of APC was less than 2.2 times prolonged when compared to aPTT in the absence of APC (APC ratio < 2.2). Digestion with a restriction enzyme of a previously amplified exon 10 of the gene that encodes for factor V was used to detect the presence of the factor V mutation. We identified 5 patients (prevalence: 7.5%) with APC resistance (mean age: 31 years, range: 6-52 years). Mutation in factor V gene was confirmed in three of them. In the control group we detected 3 (4.5%) low APC ratios, all of them carrying specific factor V mutation. We cannot conclude a significant association between APC resistance and IS [odds ratio: 1.72; χ2 Mantel and Haenszel was 0.53 (p = 0.4673) and exact Fisher’s test p = 0.3589] but these 5 young adults suffered an episode of IS having APC resistance as the only prothrombotic condition. In conclusion, these results cannot prove a statistical association between APC resistance and IS. Further studies must be done in order to confirm that there is no relationship between APC resistance and IS in young adults when major risk factors are exclud