Background and aim <p>Direct oral anticoagulants (DOACs) are now a well-established class of medication for blood clot prevention and treatment. So far, literature evaluating real-world data on the drug–drug interactions (DDIs) between DOACs and other medications in patients with pulmonary embolism (PE) is limited. This study aims to investigate these interactions in patients with PE to address this and improve patient care.</p> Materials and methods <p>In a retrospective study, patients' medications were recorded upon hospital discharge and reviewed again 3 months later. A clinical decision support system (AiDKlinik^® Release 3.5) was initially used to screen for DDIs and drug-related problems. Subsequently, medications were entered into Lexicomp^®, a comprehensive drug interaction database, to gain detailed scientific explanations and references for the identified interactions and their mechanisms. Binary logistic random intercept models were used to identify potential risk factors of drug–anticoagulation interactions.</p> Results <p>The 477 included PE patients had a median intake of five drugs. Drug–anticoagulation interactions depended strongly on the number of medications taken (<i>P</i> value &lt; 0.001). However, the association was non-linear, resulting in a saturation effect for a higher number of drugs. The odds ratio for having at least one drug–anticoagulation interaction was 0.40 (95% confidence interval 0.17–0.96; <i>P</i> value = 0.040) in patients with hypertension.</p> Conclusions <p>The potential for DDIs with DOACs represents a significant concern. By being aware of the most common interactions, risk factors and avoidance strategies, the safety and efficacy of therapy can be optimized.</p>