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Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVLG1691A), prothrombin (PTG20210A), methylenetetrahydrofolate reductase (MTHFRC677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-15G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy–Weinberg equilibrium (χ2test P>0.20). FVLG1691A and PTG20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFRC677T in homozygosis in 29 (16.2%), MTHFRA1298C in homozygosis in 13 (7.3%); PAI-15G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVLG1691A and PTG20210A as well as MTHFRC677T and PAI-14G allele were significantly associated, whereas MTHFRA1298C was not. At multivariable model including PTG20210A, MTHFRC677T and PAI-14G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a prospective trial of thromboprophylaxis in mCRC patients with high-risk genotypes.