BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been included in international guidelines as important alternatives to vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE) and stroke prevention in non-valvular atrial fibrillation (NVAF). Meanwhile, in the Netherlands, NOACs are widely used next to VKAs. The objective of our study is to estimate the cost-effectiveness of treatment with rivaroxaban compared to VKAs in NVAF and VTE patients in the Netherlands, using data from international prospective observational phase IV studies. METHODS: Two models were developed to represent NVAF and VTE patients, populated with patients from the XANTUS (NCT01606995) and XALIA (NCT01619007) international prospective observational studies. The one-year cost-effectiveness of rivaroxaban use, compared to VKAs, was explored in a population consisting of NVAF and VTE patients (base case) as well as for four scenarios with subpopulations: NVAF patients only, VTE patients only, NVAF patients with unstable international normalized ratio (INR), and NVAF patients using an INR self-measuring device. RESULTS: In the base case, rivaroxaban saved €72,350 and gained 21 quality-adjusted life-years (QALYs) in a simulation of 2,000 patients over the use of VKAs. Ergo, rivaroxaban was dominant over VKAs. The probabilistic sensitivity analysis showed a probability of 85% for rivaroxaban being dominant and 100% at a willingness-to-pay threshold of €20,000/QALY. Rivaroxaban appeared to be dominant in all scenarios as well, except for the NVAF-patients-only scenario where the incremental cost-effectiveness ratio (ICER) was €157/QALY. CONCLUSIONS: In patients with NVAF or VTE, rivaroxaban treatment is likely to be cost-effective and potentially cost-saving alternative to VKA in the Netherlands.