Venous thromboembolism (VTE) is a significant problem for surgical and medical hospitalized patients, leading to the possibility of serious illness and risk of death. The aim of the present study was to investigate soluble P-selectin levels and genetic polymorphisms in 5, 10-methylenetetrahydrofolate reductase (MTHFR 677C/T) and to evaluate its associations with VTE was the aim of work. The study involved 49 patients diagnosed as having VTE (as a patients group) as well as 24 apparently healthy volunteers (as controls group). All the participants included in the study were assessed for soluble serum P-selectin levels using the enzyme-linked immunosorbant assay technique. All the participants included in the study were genotyped for detection of MTHFR gene polymorphisms (677C > T) by restriction fragment length polymorphism. Concerning the results of soluble P-selectin, there were statistically significant differences between the two groups (P = 0.0210). Concerning the results of MTHFR gene polymorphisms, there were no statistically significant differences between the two groups regarding CT allele (P = 0.8790), but there were highly statistically significant differences between the two groups regarding CC, TT alleles as well as CC/CT and TT/CT alleles (P < 0.0001). According to our study, elevated soluble P-selectin levels as well as MTHFR gene polymorphisms are to be considered as independent risk factors for development of VTE, so it may be recommended to include P-selectin assay and detection of MTHFR gene polymorphisms when considering patients with thromboembolism even in the absence of any other predisposing factors.