Background: Venous thrombosis (VT) is one of the three principal causes of cardiovascular disease (CVD) related mortality with a significant genetic predisposition. In Europe, although overall CVD-related morbidity is decreasing, mortality is still high. Hungary shares the largest proportion of this mortality, and CVD remains the prominent cause of death in Hungary. The coexistence of heritable and non-heritable risk factors increases the burden of VT in dual-exposed individuals. Formerly conducted studies revealed that the Roma population is at higher risk of CVD due to heritable and non-heritable VT risk factors. Thus, we aimed to explore and compare the gene-environmental interactions and VTE risk in general Hungarian and Roma subjects. We further aimed to investigate the combined VT risk predictability of the five strongly associated SNPs and well-known conventional VT risk factors in the Hungarian population. Methods: A comparative cross-sectional study design was employed among 406 general Hungarian and 395 Roma subjects. Moreover, a case-control study was conducted among 298 clinically confirmed VT cases and 400 health controls to investigate the heritable background of VT in the Hungarian population. Except for the 298 subjects data; which is collected by the DCLS, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, all other included data were extracted from the comprehensive database. Plink 1.9 version and IMB SPSS version 26 were used for the analysis. Furthermore, the AUCs for genetic and non-heritable risk factors were estimated to explore their VT risk predictability in the case-control study. An odds ratio (OR) with their respective 95% CI at 0.05 alpha value was used to declare any association between VT risk and its factors. Results: In both studies, the risk allele frequencies of F5 (rs6025), F11 (rs2036914), and ABO (rs8176719) are higher in the Hungarian population. However, in the comparative study, the SERPINC1 (rs121909567) SNP risk allele is only present in the Roma population but not all in the general Hungarian population, which confirmed that the Roma population is the origin of this particular mutation. The coexistence of genetic and non-heritable risk factors increases the likelihood of VT in double-exposed individuals. Due to the multiplicative interaction between the genetic and non-heritable risk factors such as depression and rs2036914 risk variant (β=0.819, p=0.02), high levels of LDL-C and rs2066865 (FGG) (β= 0.389, p= 0.002), rs8176719 (ABO/non-O blood type and cancer (β=0.370, p<0.001), rs2066865 (FGG) and CAD (β=0.143, p= 0.046) the risk of VTE is higher for the Roma subjects than the general Hungarian subjects. However, as a result of the synergistic interaction between cigarette smoking and Leiden mutation (β= 0.172, p= 0.008), diabetes mellitus and rs8176719 (ABO) (β= 0.194, p <0.01), rs8176719 (ABO) and CAD, (β= 0.197, p= 0.009), migraine (β= 0.287, p= 0.001), and depression (β= 0.342, p <0.001) the risk of VTE significantly higher only for the general Hungarian population but not for the Roma populations. Likewise, in a case-control study, the risk allele frequencies of F5, F11, and ABO are higher among the VT cases than in the control group. Specifically, the Leiden mutation risk allele is highly prevalent among VT cases. Its risk allele frequency was 3.52-fold higher in the VT group than in the control group (AOR =3.52, 95% CI: 2.50; 4.95). The combined (genetic and non-heritable) (AUC=0.89, p<0.001) show good discrimination between VT cases and control. Conclusions: In general, our studies provide insight into VT background (heritable and non-heritable VT risk factors) in the Hungarian population. The Leiden mutation (rs6025), F11 (rs2036914), and ABO (rs8176719) determine the genetic VT risk factors in the Hungarian populations. The presence of other non-heritable VT risk factors such as aging, CAD, DM, cancer, smoking, and obesity, increases the likelihood of VT risk in dual-exposed individuals compared to their counterparts. The combined model predicts the risk of VT risk in the Hungarian population. Recommendations Stratification of highly vulnerable individuals based on their genetic profiling and comorbidities are of paramount importance for the efficient and effective utilization of scarcely available VT risk controlling and preventive measures in the Hungarian population. Furthermore, we suggest further study that considers the novel and strongly associated VT SNPs and the formerly identified SNPs and their comparison on the VT risk predictability in the Hungarian population