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★ Evaluation of IL-6 and MMP-9 polymorphisms in cancer patients DVT+ and DVT−. ★ Changes in plasma levels of IL-6 and MMP-9 in cancer patients DVT+ and DVT−. ★ We show the significant role of the cytokine IL-6 in MMP-9 activation. ★ IL-6 and MMP-9 polymorphisms may be useful in cancer patients management.A growing body of evidence shows an increased risk of deep vein thrombosis (DVT) among cancer patients. Novel markers are needed to identify patients prone to develop DVT. The aim of the present study was to determine whether IL-6–174 G > C and MMP-9–1562 C > T polymorphisms may influence the development of DVT in cancer patients.Polymorphisms of IL-6 and MMP-9 were analyzed in 320 DNA samples from cancer patients (DVT+ and DVT−) and in 215 healthy donors. IL-6 and MMP-9 plasma levels were also measured by ELISA.Distribution of −174 IL-6 genotype and −1562 MMP-9 were similar between healthy controls and DVT− cancer cases (OR = 0.98 and 1.04, respectively). Different results were obtained by compared healthy controls with DVT+ cancer patients. −174 IL-6 GG polymorphism was associated to DVT (OR = 2.07; 95% CI: 1.30–3.30), as well as −1562 MMP-9 CC polymorphism (OR = 2.60; 95% CI: 1.48–4.57).The results of the present study support a model in which the GG and CC genotypes, respectively for IL-6–174 G > C and MMP-9–1562 C > T polymorphisms, are associated with a risk of DVT in cancer patients by inducing the release of IL-6 with subsequent increment of MMP-9. Overall, these findings may contribute to the management of DVT in cancer patients.