Atrial fibrillation (AF) is linked to an elevated risk of thromboembolic events. Despite the use of guideline-recommended direct anticoagulants (DOACs), a significant proportion of AF patients show a residual risk of thromboembolic events, driven by mechanisms that are not fully understood.We conducted a pilot study to characterize the platelet function in DOACs-treated AF patients, to explore whether an association between platelets and the residual thromboembolic risk exists.Within the Age-It project of the National Recovery and Resilience Plan, we examined by flow cytometry the platelet phenotype, reactivity, and mitochondrial function and quantified 12 inflammatory cytokines of individuals with DOACs-treated permanent AF without a history of stroke (n = 18, 66 ± 13 years, 39% females), compared with an age-, sex-, and comorbidity-matched control group without AF (n = 18, 65 ± 11 years, 39% females).Unstimulated circulating platelets of DOACs-treated AF displayed a low-adhesive phenotype compared with matched controls. Upon stimulation, platelets of DOACs-treated AF were hyporeactive to ADP and PAR1 stimulation, but hyper-reactive to GPVI stimulation (adjusted p < 0.01). The lower responsiveness to ADP correlated with increased plasmatic concentrations of IFN-γ (r = - 0.539; p < 0.05) and TNF-α (r = - 0.472; p < 0.05). The higher reactivity to GPVI associated with an increased mitochondrial function, which positively correlated with TNF-α levels.Individuals with AF treated with DOACs exhibit low-grade inflammation and an altered platelet reactivity, suggesting a potential mechanism behind their residual thromboembolic risk. Further well-powered studies are warranted to test whether the observed platelet phenotype is implicated with the residual thromboembolic events in DOACs-treated AF patients.