Background: Venous thromboembolism (VTE) causes substantial morbidity and mortality in patients with cancer. The guidelines for the treatment of VTE in cancer patients recommend low molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) for patients where major bleeding is a low risk factor. Several studies show that DOAC represent a convenient and effective treatment option in alternative to LMWH in patients with deep-vein thrombosis or pulmonary embolism. Even though some recent studies have compared the effectiveness of DOAC vs LMWH, there is no available a cost-effectiveness analysis (CEA) comparing the relative effectiveness and cost-effectiveness of apixaban, other DOAC and. LMWH. The study aim was to conduct a CEA of apixaban (API), edoxaban (EDO), rivaroxaban (RIVA) and LMWH for the treatment of cancer associated VTE in Spain. Methods: We developed a Markov model with 12 transition health states. The model has been face-validated by two oncologists from two different Spanish hospitals. The use of resources and costs were obtained from the 2021 Spanish Ministry of Health database, and the main references for obtaining the outcomes were derived from CARAVAGGIO, HOKUSAI-VTE, ADAM VTE and SELECT-D trials. Our model yielded the effectiveness score in terms of cost per life-year (LY) gained and cost per quality-adjusted for life-year (QALY) gained. The time horizon was 12 months. We performed a deterministic and probabilistic sensitivity analysis to validate the robustness. Results: API showed the lowest 12-month cost (1943 €), and the highest amount of life years (0.79) and highest amount of QALY (0.55) gained. RIVA and EDO were less effective in terms of LY (0.76 and 0.74, respectively) and QALY (0.53 and 0.52, respectively) gained than LMWH (LY of 0.76 and QALY of 0.53), and less costly. The Incremental Cost-Effectiveness Ratio (ICER) scores in terms both of €/LY and €/QALY gained show that API is dominant over LMWH, RIVA and EDO. Conclusions: Our results suggest that API is more effective and more cost-effective than LMWH, RIVA or EDO with the 2021 Spanish healthcare costs. For interpretation of the results, reader must consider that the costs of resources analyzed in this paper may vary from country to country, and dabigatran was not included in the analysis since there are not cancer associated VTE clinical trials with dabigatran data to calculate CEA from.