Based on their mode of action, it is reasonable to expect that the combination therapy of aspirin and a vitamin K antagonist (VKA) may be more beneficial in preventing (athero) thrombotic complications in high-risk patients for cardiovascular events. However, there is no consensus about additional aspirin use in the most common indications for VKA or the use of VKAs to be added to the most common aspirin indications. The variation in clinical outcomes and bleeding complications suggests that extrapolating from one indication to another may not be appropriate. So far, decisions about the combined use of aspirin and VKA are individualized in the absence of adequate data. Only in patients with mechanical heart valves the benefits and safety of combining aspirin with VKA therapy seems obvious. In patients with peripheral artery disease no beneficial effect was noted for the combination therapy, perhaps with an exception of those with graft failure. For all other clinical situations, this is unclear and should be avoided.