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Background: Direct oral anticoagulants (DOACs) have demonstrated clinical benefits and better patient adherence over low-molecular-weight heparin (LMWH) in treating patients with cancer-associated venous thrombosis (CAT). We aimed to compare the cost-effectiveness of DOACs against LMWH in patients with CAT from the perspective of the Hong Kong healthcare system., Methods: A Markov state-transition model was performed to estimate the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) for DOACs and LMWH in a hypothetical cohort of 10,000 patients with CAT over a 5-year lifetime horizon. The model was primarily based on the health states of no event, recurrent venous thromboembolism, bleeding, and death. Transition probabilities, relative risks, and utilities were derived from the literature. Resource cost data were obtained from the Hong Kong Hospital Authority. Deterministic and probabilistic sensitivity analyses tested the robustness of the results., Results: Relative to LMWH, DOACs were associated with increased QALYs (1.52 versus 1.50) at a lower medical cost of USD 2,232 versus 8,224 in five years. The cost of LMWH was the main contributor to the outcome. Out of 10,000 simulated cases, DOACs were dominant in 15.8% and cost-effective in 42.1%, at the willingness-to-pay threshold of USD 148,392 per additional QALY., Conclusions: DOACs were associated with greater QALY improvements and lower overall costs compared to LMWH. Accounting for uncertainty, DOACs were between cost-effective and dominant in 57.9% of cases. DOACs are a cost-effective alternative to LMWH in the management of CAT in Hong Kong., Competing Interests: ICK Wong received research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, the European Commission, the National Health and Medical Research Council in Australia and the European Union's Seventh Framework Programme for research and technological development. He has also received consulting fees from IQVIA, the WHO and expert testimony for the Appeal Court in Hong Kong over the past three years. He is an advisory member of the Pharmacy and Poisons Board, the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization and the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government. He is also a non-executive director of Jacobson Medical Hong Kong Advanced Data Analytics for Medical Science (ADAMS) Limited and OCUS Innovation Limited (Hong Kong, Ireland and United Kingdom) and the founder and director of Therakind Limited (United Kingdom). EWC reported receiving grants from the Research Grants Council of Hong Kong, the Research Fund Secretariat of the Food and Health Bureau of Hong Kong, the National Natural Science Fund of China, the National Health and Medical Research Council (Australia), Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, Takeda, Novartis, Wellcome Trust and Narcotics Division of the Security Bureau of Hong Kong; honorarium from Hospital Authority; outside the submitted work. Other authors report there are no competing interests to declare., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)