Background: Most commercially available drug-interaction screening systems have important limitations that fail to protect patients from dangerous drug combinations. We attempted to overcome the limitations of our commercial program by developing a Web-based clinical information system to serve as a safety net. This system identifies drug interactions with newly marketed medications not screened by our commercial program, and generates a second alert on dangerous interactions that were overridden during order processing. Methods: The Web-based system uses patient-specific pharmacy, laboratory, and demographic data to generate detailed alerts on patients receiving potentially dangerous drug combinations. The system's impact on the use of dangerous drug combinations and related adverse events was evaluated by a retrospective analysis of patients receiving cisapride with contraindicated medications in the 2 years before and after implementation. Results: The rate of dangerous drug combinations declined by 66% after implementing the system, from 9.0% of cisapride orders in 1994 and 1995 to 3.1% in 1996 and 1997 (P<.001). The mean [SD] duration of contraindicated therapy (4.1 [3.8] vs 1.6 [1.4] days, P<.001) and proportion of patients being discharged under treatment with a dangerous drug combination (36.2% vs 7.7%, P< .001) was also significantly reduced during the study period. Three patients (1.7%) during the control period experienced serious adverse events that may have been related to the targeted drug interactions. No symptomatic cardiac events were identified during the study period (P = .21). Conclusions: An automated system running as a safety net can be an efficient method of detecting contraindicated drug combinations and serves an important role in the avoidance o f potentially serious adverse drug events.