Background: Preventing the use of medications where there is the potential for serious drug-drug interactions or drug-disease interactions (contraindications) is essential to ensure patient safety. Previous studies have looked at the incidence of prescribing contraindicated drug combinations, but little is known about the underlying reasons for the co-prescribing events. The objectives of this study were to estimate the incidence of prescribing contraindicated drug combinations in general practice and to explore the clinical context, possible causes and potential systems failures leading to their occurrence. Methods: A list of contraindicated drug combinations was compiled according to established references. A search of computerised patient medication records was performed, followed by detailed chart review and assessment. The patient records from four general practices in an area of England were searched for a period of I year (I June 1999-31 May 2000) to identify contraindicated drug combinations. All patients registered with the four participating practices during the study period were included (estimated n = 37 940). Medical records of the cases identified by the computer search were reviewed in detail and relevant information was extracted. Each case was then independently assessed by a pharmacist and a physician who judged whether the co-prescribing was justified and whether it was associated with an adverse drug event. Proximal causes and,potential systems failures were suggested for each co-prescribing event.. Main outcome measures and results: Fourteen patients with potential drug-drug interactions and 50 patients with potential drug-disease interactions were identified. Overall, these represent an incidence of 1.9 per 1000 patient-years (95% Cl 1.5, 2.3) or 4.3 per 1000 patients being concurrently prescribed greater than or equal to2 drugs per year (95% Cl 3.2, 5.4). 62 cases involving 63 co-prescribing events were reviewed. Two-thirds of these events involved medications that were initiated by hospital doctors. Awareness of the potential drug-drug or drug-disease interactions was documented in one-third of the events at the time of initial co-prescribing. Within the study period, the co-prescribing was judged to be not justified in 44 events (70%). Potential drug-drug interactions possibly resulted in two adverse drug events. The majority of contraindicated co-prescribing related to drug-disease interactions involved the use of propranolol or timolol eye drops for patients receiving bronchodilators and the use of amiodarone for patients receiving levothyroxine sodium. Conclusion: The prescribing of contraindicated drug combinations was relatively rare in this study. Multiple possible causes and systems failures were identified and could be used to develop strategies for the prevention of prescribing errors involving contraindicated drug combinations in primary care.