Background Information regarding the significance of platelet (PLT) count on outcome of atrial fibrillation (AF) patients who are treated with anticoagulants is limited. Methods We conducted a monocentric observational retrospective cohort study of AF patients treated with either warfarin (n = 6287) or non-vitamin K antagonist oral anticoagulants (NOACs) (n = 5240). Patient were divided into 3 subgroups; low, normal and high PLT for counts < 150 K/ μl, 150–450 K/ μl and > 450 K/ μl, respectively. A multivariate Cox-regression was used to evaluate the association between PLT subgroups and clinical outcomes. Results During follow-up [median = 40.6 months (IQR 17.6–60)], mortality (HR 1.36, 95 CI 1.1–1.74, p = 0.01) and rate of myocardial infarction (MI) (HR 2.4, 95 CI 1.28–4.57, p = 0.007) were higher in patients with high compared to normal PLT. Transient ischemic attack or cerebrovascular accident (TIA/CVA) rate was lower in patients with low compared to normal PLT (HR 0.69, 95 CI 0.51–0.93, p = 0.02). A comparison between NOACs and warfarin demonstrated a significantly better clinical outcome for patients on NOACs in both the low (lower mortality rates) and normal PLT subgroup (lower mortality, TIA/CVA and systemic emboli rates). For patients on NOACs, low and high compared to normal PLT were associated with a higher combined outcome (HR 1.12, 95 CI 1–1.38, p = 0.047), and a higher systemic emboli rate (HR 7.07, 95 CI 1.66–30.25, p = 0.008), respectively. Conclusions Abnormal PLT count is associated with different clinical outcome of AF patients on anticoagulants. Further studies are needed in order assess whether PLT level should influence strategies of anticoagulation.