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Simple Summary: The duration of anticoagulant treatment for venous thromboembolism in cancer patients is not well defined. The decision to suspend or re-introduce anticoagulation is based on an individual assessment between thrombotic and hemorrhagic risk. In this study, three biomarkers have shown the ability to help the clinician in decision making. Although these results should be evaluated in further studies, they open up a possibility of change in the management of cancer associated thrombosis patients. The most appropriate duration of anticoagulant treatment for cancer-associated venous thromboembolism (CAT) remains unclear. We have conducted a prospective multicenter study in CAT patients with more than 6 months of anticoagulant treatment to predict the risk of venous thromboembolism (VTE) recurrence after anticoagulation discontinuation. Blood samples were obtained when patients stopped the anticoagulation, at 21 days and at 90 days. In each sample we assessed different coagulation-related biomarkers: D-dimer (DD), high-sensitivity C-reactive protein (hs-CRP), P-selectin (PS), phospholipids, soluble tissue factor, factor VIII and the thrombin generation test. It was evaluated 325 CAT patients and 166 patients were included in the study, mean age 64 ± 17 years. VTE recurrence until 6 months after stopping anticoagulation treatment was 9.87% [95% confidence interval (CI): 6–15]. The biomarkers sub-distribution hazard ratios were 6.32 for ratio DD basal/DD 21 days > 2 (95% CI: 1.82–21.90), 6.36 for hs-CRP > 4.5 (95% CI: 1.73–23.40) and 5.58 for PS > 40 (95% CI: 1.46–21.30) after 21 days of stopping anticoagulation. This is the first study that has identified the DD ratio, hs-CRP and PS as potential biomarkers of VTE recurrence in cancer patients after the discontinuation of anticoagulation treatment. A risk-adapted strategy may allow the identification of the optimal time to withdraw the anticoagulation in each CAT patient. [ABSTRACT FROM AUTHOR]