Background <p>Left atrial appendage (LAA) thrombus formation is associated with elevated stroke risk and mortality. This study was designed to compare different therapeutic strategies in patients presenting with LAA thrombi despite adequate oral anticoagulation (OAC) therapy.</p> Methods <p>In this retrospective single-center study, patients with atrial fibrillation (AF) and LAA thrombus despite adequate OAC for more than three weeks were identified. A follow-up transesophageal echo (TEE) was performed at least four weeks after the initial TEE. Thrombus resolution was assessed for each treatment cycle, defined as the interval of OAC therapy between two consecutive TEE examinations.</p> Results <p>The study included 216 patients who underwent a total of 294 treatment cycles. At baseline, 47% (<i>n</i> = 101) of patients were receiving novel oral anticoagulants (NOACs), while 53% (<i>n</i> = 115) were treated with vitamin-K antagonists (VKAs). Treatment options included switching OAC from VKA to NOAC (<i>n</i> = 18), from NOAC to a different NOAC (<i>n</i> = 14) and from NOAC to VKA (<i>n</i> = 77); or maintaining the same NOAC (<i>n</i> = 28) or VKA (<i>n</i> = 157). Overall, LAA thrombi resolved in 70% (152/216) after a mean follow up time of 130 (SD 195) days). No significant differences regarding resolution rate between the five different anticoagulation strategies were observed (<i>p</i> = 0.866). Multivariate regression analysis identified tricuspid annular plane systolic excursion as independently predictive of LAA thrombus persistence (OR 0.87; 95% CI 0.78–0.98; <i>p</i> = 0.026).</p> Conclusion <p>This is the largest cohort of patients presenting with LAA thrombi despite adequate OAC. Overall resolution was 70%. Modification of the anticoagulation regimen did not result in higher thrombus resolution rates compared with continuation of the same therapy.</p> Graphical Abstract <p></p>