Introduction: Severely injured elderly patients have a poorer prognosis and higher mortality rates after severe trauma compared with younger patients. The aim of this study was to correlate the influence of pre-existing oral anticoagulation (OAC) and antiplatelet drugs (PAI) on the outcome of severely injured elderly patients. Methods: Using a prospective cohort study model over an 11-year period, severely injured elderly patients (>= 65 years and ISS >= 16) were divided into two groups (no anticoagulation/platelet inhibitors: nAP and OAC/PAI). A comparison of the groups was conducted regarding injury frequency, trauma mechanism, severity of head injuries, and medication-related mortality. Results: In total, 254 out of 301 patients were analyzed (nAP: n = 145; OAC/PAI: n = 109, unknown data: n = 47). The most relevant injury was falling from low heights (<3 m), which led to a significantly higher number of severe injuries in patients with OAC/PAI. Patients with pre-existing OAC/PAI showed a significantly higher overall mortality rate compared to the group without (38.5% vs. 24.8%; p = 0.019). The severity of head injuries in OAC/PAI was also higher on average (AIS 3.7 +/- 1.6 vs. 2.8 +/- 1.9; p = 0.000). Conclusion: Pre-existing oral anticoagulation and/or platelet aggregation inhibitors are related to a higher mortality rate in elderly polytrauma patients. Low-energy trauma can lead to even more severe head injuries due to pre-existing medication than is already the case in elderly patients without OAC/PAI.