Background: Thrombophilia is a hypercoagulable state that may have a genetic basis (inherited) or can be acquired. It is a multifactorial condition and only the mutual interactions between the environment and genes may lead to the development of clinical manifestation. This state is the main factor that promotes venous (rarely arterial) thromboembolism (VTE). The inherited thrombophilia is mainly associated with two pathogenic variants in the V coagulation factor (FV) and the prothrombin (FII) genes. The aim of our study was to evaluate the frequency of two pathogenic variants in FII and FV genes as an inherited thrombophilia factor in a representative group of Polish population in comparison with other described populations. Methods: All studied groups consisted of 1414 unrelated patients at the age between 18 and 70. The individuals from the research group came from the Podlasie region of Poland. Genotyping of FII, FV and MTHFR variants was performed using the 7900HT Fast Real-Time PCR System and were genotyped by TaqMan assay. Results: The pathogenic allele frequency for A allele was 0.03 (3%) and 0.07 (7%) for FII and FV genes, respectively. The GA/AA genotypes (c.*97G>A variant) were observed only in 33 (5.03%) individuals in the studied group. Additionally, the frequency of GA/AA genotypes was over 17.4% in the coagulation factor V. Co-instability of heterozygous genotype GA of variants FII and FV genes was observed only in 4 subjects. Conclusions: Our results is similar to the frequency of the both FII and FV variants in the South–Eastern European countries population, whose value is about 5% and 2.5% respectively.