BACKGROUND: The safety of early initiation of anticoagulant therapy in patients with ischaemic stroke related to atrial fibrillation (AF) is unknown. We investigated the safety of early initiation of direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs) or no anticoagulation. METHODS: This observational, retrospective, single-centre study included consecutive patients with recent (< 4 weeks) ischaemic stroke and AF. The primary outcome was the rate of major (intra- and extracranial) bleeding in patients on different treatment schemes: DOACs, VKAs and not anticoagulated. We also investigated the rate of ischaemic cerebrovascular events and mortality. RESULTS: We included 959 consecutive patients with AF and ischaemic stroke followed up for an average time of 16.1 days after the index event. 559 patients of 959 (58.3%) were anticoagulated with either VKAs (259) or DOACs (300). Anticoagulation was started after a mean time of 7± 9.4 in the DOACs group and 11.9± 19.7 in the VKAs group. Early initiation of any anticoagulant was not associated with an increased risk of any major bleeding (OR 0.49; CI, 0.21-1.16) and in particular of intracranial bleeding (OR 0.47; CI, 0.17-1.29; p = 0.143) compared with no anticoagulation. In contrast to VKAs (OR 0.78; CI, 0.28-2.13), treatment with DOACs (OR 0.32; CI, 0.10-0.96) reduced the rate of major bleeding compared to no-anticoagulation. Early recurrences of ischaemic stroke did not differ significantly among the three groups. CONCLUSIONS: Starting DOACs within a mean time of 7 days after stroke appears safe. Randomised controlled studies are needed to establish the added efficacy of starting anticoagulation early after stroke.