Background Drug-disease interactions are situations where pharmacotherapy may have a negative effect on patients' comorbidities. In these cases, it can be necessary to avoid that drug, adjust its dose or monitor therapy. In the Netherlands, pharmacists have developed a best practice how to systematically evaluate drug-disease interactions based on pharmacological considerations and implement recommendations for specific drug-disease interactions. Aim To describe the development of recommendations for drug-disease interactions and the implementation in prescribing and dispensing practice in the Netherlands. Setting Pharmacies and physicians' practices in primary care and hospitals in the Netherlands. Development A multi-disciplinary expert panel assessed if diseases had clinically relevant drug-disease interactions and evaluated drug-disease interactions by literature review and expert opinion, and subsequently developed practice recommendations. Implementation The recommendations were implemented in all clinical decision support systems in primary care and hospitals throughout the Netherlands. Evaluation Recommendations were developed for 57 diseases and conditions. Cardiovascular diseases have the most drug-disease interactions (n = 12, e.g. long QT-syndrome, heart failure), followed by conditions related to the reproductive system (n = 7, e.g. pregnancy). The number of drugs with recommendations differed between 6 for endometriosis and tympanostomy tubes, and up to 1171 in the case of porphyria or even all drugs for pregnancy. Conclusion Practice recommendations for drug-disease interactions were developed, and implemented in prescribing and dispensing practice. These recommendations support both pharmacists and physicians by signalling clinically relevant drug-disease interactions at point of care, thereby improving medication safety. This practice may be adopted and contribute to safer medication use in other countries as well.