Introduction: Gene mutations for methylentetrahydrofolate reductase (MTHFR) 677CT and 1298 AC cause thermal lability and reduced enzyme activity. Homozygous carriers of genotypes TT and CC exhibit elevated homocysteine in plasma, and together with folate deficiency and vitamin B12 is a risk factor for the development of venous thromboembolism (VTE), one of the leading causes of stroke and mortality in the world. Research Objectives: Investigate the incidence of MTHFR mutations C677T and A1298C in the Croatian population and their individual/combined effect on thrombotic risk and the correlation of mutations C677T and FV Leiden as a combined risk factor for VTE development. Materials and Methods: Following approval from the Ethics Committee and the informed consent, a case-control study was conducted among a group of 152 patients with clinically and laboratory confirmed VTE diagnoses as well as a control group of 101 voluntary blood donors without thromboembolic episodes. After DNA isolation using QIAamp DNA Blood mini kits on the QIAcube instrument (Qiagen, Germany), genotype mutations were determined using RT-PCR (real-time polymerase chain reaction) on the ABI 7500 Real-Time PCR System (Applied Biosystems, USA). Results: The frequency of genotypes MTHFR C677T and A1298C, as well as the frequency of T and C allele, did not exhibit a statistically significant difference between patient groups and the controls. Comparing combinations for MTHFR C677T and A1298C genotypes did not show any statistical significance among the observed groups. Not one VTE patient was a carrier of both homozygous genotype MTHFR mutations. Our results did not show a correlation between VTE patients who are carriers of the factor V Leiden (G1691A) and MTHFR 677TT and the risk of VTE. Conclusion: Our results did not provide evidence of any effects from either single or combined mutations on the thrombotic risk of venous thromboembolism.