Although the On-X aortic valve (AO) is considered less thrombogenic compared to its counterparts, we present a case where recurrent thromboembolic ischemic stroke occurred, first with a slightly sub-therapeutic, then even with an elevated International Normalized Ratio (INR). A 36-year-old male, the background of On-X AO replacement but no other risk factors, developed thromboembolic stroke twice while on Warfarin, first with INR 1.4, second with INR 2.4. Despite extensive investigation, other than elevated levels of low-density lipoproteins, no other treatable cause was found with the latter episode. The INR range was increased to 2.5-3.5, and aspirin and statin were added. The occurrence of thromboembolic stroke with an On-X AO despite maintaining an INR of 2.4, presents a dilemma for future prevention. The American Heart Association (AHA) and the American College of Cardiology (ACC) guidelines for thromboembolism prevention in case of an On-X AO recommend an INR range of 1.5-2 as being effective when warfarin is used along with aspirin. The take-home message is that the recommendation of an INR range of 1.5-2 with an On-X AO should be approached with caution; aspirin should be strongly considered regardless of the presence of thromboembolic risk factors. Patients developing thromboembolism have a high risk of recurrence. Therefore, a higher INR, along with the addition of aspirin and statin should be considered. Studies are needed to establish guidelines for a reliable INR range in these scenarios., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hashmi et al.)