Background: Translation of rational drug therapy into practice remains an international problem. Although pharmacotherapeutic treatment guidelines (PTGs) as managerial tools are favoured over hospital drug formularies (HDFs), the latter are still applied in most hospitals. HDF enforcement often leads to timeconsuming consultation from the perspective of both pharmacy sta and prescriber. So far, research on HDFs has only been conducted outside Europe. Moreover, this research has only been descriptive. Straightforward indicators qualitatively characterising HDF non-adherence have never been assessed. Methods: A retrospective 1:1 case-control study was conducted across three general teaching hospitals. Non-HDF requests were compared with HDF requests. Data were multivariably analysed, considering patient, prescriber, drug, and HDF characteristics as possible indicators for non-adherence. Results: HDF adherence was almost universal across characteristics. Non-adherence was characterised by newly marketed drugs, drugs that were part of patients' pre-admission drug therapy, drugs with many fellow drugs within the drug group on the market, and drugs originating from a drug group for which the HDF was highly restrictive. Contrary to common perception, nonadherence was independent of medical specialty, therapeutic area, and patient characteristics. Conclusion: This research provides an epidemiological framework for hospitals (drug and therapeutics committees) for evaluating pharmacy data on HDF nonadherence. It can be used for educational tailor-made feedback to prescribers and for drug selection when the inclusion of newly marketed drugs is considered or HDF restrictiveness for certain drug groups is reconsidered. Moreover, it demonstrates the importance of a regional approach involving secondary and primary health care to establish continuity in seamless care of drug therapy.