Background:Ischemic cerebrovascular stroke (IS) is a polygenic multifactorial disease; effect of thrombotic gene polymorphism, platelet activation and reactivation synergistic risk effect are plausible postulation.Aims:To assess synergistic effect of FVL and MTHFR genes polymorphisms and platelet activity and reactivity as risk factors for ischemic cerebrovascular strokeMethods:A hospital‐based case‐control study; approvered by Suez Canal University (SCU) ethical committee, after obtaining an informed consent. 120 individuals were included: 60 acute IS patients, subdivided into 2 subgroups regarding the vascular risk factors recruited from neurology department, SCU Hospital; and 60 matched healthy individuals. FVL G1691A, FVLA4070G, FVL A5279G, MTHFRC677T, and MTHFR A1298C were assessed using multiplex real‐time PCR assay (AnyplexTM II Thrombosis SNP Panel Assay, seegene); platelet ex vivo activity & reactivity (CD62P; after ADP provocation) were assessed by four‐colors flow cytometry, FACS Caliber, BD‐Biosciences).Results:Both FVLG1691A & FVL A4070G (OR 19.6; 95 % CI = 2.5 to 154.4; p = 0.0001), (OR 7.6; 95 % CI = 1.13 to 178; p = 0.012), and MTHFRC677T (OR 10; 95 % CI = 1.16to 85.8; p = 0.03) and MTHFRA1298C (OR 11.6; 95 % CI = 1.35to 100.7; p = 0.03) & the presence of >1 mutation (p < 0.0001) showed a statistically significant association with IS. Multivariate logistic regression models showed that studied SNPs add synergistic effect on the vascular risk factors. A statistically significant difference was detected in platelet CD62p % after adding ADP (IS patients: 72.95 ± 14.8 ‐ controls: 62.2 ± 11.39), MFI IS patients: 248 ± 101‐controls 215 ± 75.8). both FVLG1691A and MTHFRC677T were significantly associated with higher baseline platelet activation in the co‐dominant and recessive models for FVLG1691A and in the dominant model for MTHFRC677TSummary/Conclusion:FVLG1691A, FVL14070G, MTHFRC677T & MTHFRA1298C were independent risk factors for IS especially in younger patients & existence of >1 mutation significantly increased IS risk, platelet activity and reactivity and genetic polymorphism play a potential synergistic role increasing the risk of IS.image