<p>Direct oral anticoagulants (DOACs) are widely prescribed in primary care, but co-prescription with interacting drugs may increase thromboembolic and major bleeding risks. We conducted a retrospective cohort study in Belgium in 2022–2023 using the real-world THIN database to evaluate the prevalence of DOAC-related drug-drug interactions (DDIs) in general practitioners’ (GPs) prescriptions for patients with non-valvular atrial fibrillation (NVAF) and to assess factors associated with pharmacodynamic DDIs. DDIs were defined as the co-prescription of a DOAC and an interacting drug within the same week. Factors associated with pharmacodynamic DDIs were assessed using multivariable logistic regression. Among 5,637 patients receiving 13,334 DOAC prescriptions, 22.9% had at least one DDI during the year. Overall, 17.8% of GP-issued DOAC prescriptions involved a DDI, of which 91.5% were pharmacodynamic. The most frequently interacting drug classes were selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors (44.2%), antiplatelets (22.6%) and non-steroidal anti-inflammatory drugs (19.6%). Higher CHA₂DS₂-VASc score and receiving multiple DOAC types were associated with higher odds of pharmacodynamic DDIs, whereas edoxaban use and older age were associated with lower odds. Most DOAC-related interactions in primary care involved bleeding-risk drugs highlighting the need to prioritizing identification and review of these high-risk associations to support safer anticoagulation prescribing.</p>