Abstract Background Recent guidelines state that in patients with surgical biological aortic valve replacement (AVR), the use of anti-platelet therapy is as a valid alternative to postoperative anticoagulation (AC) in the absence of a further indication for AC. However, the prognostic impact of different anti-thrombotic strategies after biological AVR has not clearly been investigated so far and outcome data remain scare and inconclusive. Moreover, the AC strategy of patients presenting with post-operative atrial fibrillation (POAF), has not been investigated so far. Therefore, we aim to picture the therapeutic AC approach after biological AVR and whether the presence of POAF effects decision making with regard to anti-thrombotic management. Methods Within this prospective observational study 515 patients undergoing elective cardiac valve and or coronary artery bypass graft (CABG) surgery were enrolled. All patients were continuously screened for the development of POAF and followed until the primary endpoint (mortality) was reached. Logistic regression analysis was performed to elucidate the effect of AC on outcome. Results A total of 200 individuals underwent biological AVR (including 81 [40.3%] combined AVR+CABG surgeries, median age: 77 years [IQR: 71–80 years]; 133 [66.3%] male gender). 97 (48.3%) patients received therapeutic AC at the time of discharge, including 42 (43.4%) on vitamin K antagonists (VKA), 53 (54.6%) on low-dose low-molecular weight heparin (LMWH) and 2 (2.0%) non-vitamin K antagonist oral anticoagulants (NOACs). 103 (51.2%) patients received another anti-thrombotic approach including 23 (22.3%) on dual anti-platelet therapy (DAPT) and 72 (69.9%) with prophylactic LMWH. Interestingly, the fraction of patients that received AC were comparable between POAF (CHA2DS2-Vasc score 4, IQR: 3–5) and non-POAF individuals (51.9% vs. 44.6%; p=0.304). After a median follow-up time of 1069 days (IQR: 673–1475 days) 21 patients (10.4%) died, referring to 9 (8.3%) non-POAF and 12 (13.0%) POAF individuals. We found that a therapeutic AC after surgery showed a strong and inverse association with 3-year mortality with a crude odds ratio (OR) of 0.31 (95% CI 0.12–0.79; p=0.015). The prognostic potential remained stable after adjustment for potential confounders (p=0.029). Conclusion Therapeutic AC showed a strong and independent inverse association with 3-year mortality, mirroring a potential benefit on outcome compared to anti-platelet therapy or low-dose LMWH. However, the fraction of patients receiving therapeutic AC was considerably low – especially NOACs were not commonly used. Despite its association with fatal cardiac adverse events, the presence of POAF was not a relevant value for decision making for the initiation of AC. Further prognostic data on both thromboembolic and bleeding events are needed to elucidate a net-benefit of therapeutic AC in patients with surgical biological AVR who have an indication for AC or present with POAF. Kaplan-Meier Survival plot Funding Acknowledgement Type of funding source: None