Background Cerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC). Methods Observational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists VKAs vs. direct oral anticoagulants DOACs) with clinical outcome. Results Of 310 AF-stroke patients treated with OAC DOACs: n = 234 (75%); VKAs: n = 76 (25%), CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 1.614; 8.277; p = 0.002; DOACs: HR 2.230 1.233; 4.034; p = 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups VKAs 13/20(65%) vs. DOACs 19/66(29%); p < 0.01. The VKA-group had a 2-fold higher IS VKAs:4 (20%) vs. DOACs:6 (9%); p = 0.35 and a 10-fold higher ICH rate VKAs: 3 (15%) vs. DOACs: 1 (1.5%); p = 0.038. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 0.17; 0.94; p = 0.04). Conclusions In AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs. Clinical trial registration http://www.clinicaltrials.gov , Unique identifier: NCT03826927.