Several direct oral anticoagulants (DOACs) have been approved by the European Medicines Agency since 2008. The aim of the present cost-effectiveness-analysis was to analyze apixaban compared to other DOACs and vitamin K antagonists (warfarin) in Austria. A cost-utility-model was developed to simulate lifetime-costs and quality-adjusted-life-years of DOACs and warfarin, based on a published Markov-Model and 23 randomized trials with 94,656 atrial-fibrillation (AF) patients. Each year, a patient has a probability of suffering a clinically relevant (extracranial) bleed, an intracranial hemorrhage (ICH), an ischemic stroke or a myocardial infarction (MI), remaining healthy, or deceasing. Direct-costs (2018€) were derived from published sources from the payer’s perspective. In the base-case, warfarin had the lowest cost of 12,968 € (95%-CI±593 €) followed by apixaban (15,269 €±661 €), edoxaban (15,534 €±641 €), dabigatran (15,687 €±667 €), and rivaroxaban (17,522 €±764 €). Apixaban had the highest quality-adjusted-life-years estimate at 5.45 (SD, 0.06). In a Monte-Carlo probabilistic sensitivity analysis, apixaban was cost-effective vs. edoxaban, dabigatran, warfarin, and rivaroxaban in 85.6%, 79.0%, 76.4%, and 61.2% of the simulations, respectively. In patients with AF and an increased risk of stroke, prophylaxis with apixaban was highly cost-effective from the perspective of the Austrian health-care system.