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Drug-drug interaction (DDI) screening programs are an important tool to check prescriptions of multiple drugs. The objective of the current study was to critically appraise several DDI screening programs.A DDI screening program had to fulfil minimal requirements (information on effect, severity rating, clinical management, mechanism and literature) to be included into the final evaluation. The 100 most frequently used drugs in the State Hospital of Baden, Switzerland, were used to test the comprehensiveness of the programs. Qualitative criteria were used for the assessment of the DDI monographs. In a precision analysis, 30 drugs with and 30 drugs without DDIs of clinical importance were tested. In addition, 16 medical patient profiles were checked for DDIs, using Stockley's Drug Interactions as a reference.Suitability of DDI screening program (quality of monographs, comprehensiveness of drug list, statistical evaluation).Out of nine programs included, the following four fulfilled the above mentioned criteria: Drug Interaction Facts, Drug-Reax, Lexi-Interact and Pharmavista. Drug Interaction Facts contained the smallest number of drugs and was therefore the least qualified program. Lexi-Interact condenses many DDIs into one group, resulting in less specific information. Pharmavista and Drug-Reax offer excellent DDI monographs. In the precision analysis, Lexi-Interact showed the best sensitivity (1.00), followed by Drug-Reax and Pharmavista (0.83 each) and Drug Interaction Facts (0.63). The analysis of patient profiles revealed that out of 157 DDIs found by all programs, only 18 (11%) were detected by all of them. No program found more than 50% of the total number of DDIs. A further evaluation using Stockley's Drug interactions as the gold standard revealed that Pharmavista achieved a sensitivity of 0.86 (vs Drug Interaction Facts, Lexi-Interact and Drug-Reax with a sensitivity of 0.71 each) and a positive predictive value of 0.67.None of the four DDI screening programs tested is ideal, every program has its strengths and weaknesses, which are important to know. Pharmavista offers the highest sensitivity of the programs evaluated with a specificity and positive predictive value in an acceptable range.