BACKGROUND Drug-drug interactions (DDIs) are very prevalent in hospitalized patients. OBJECTIVE To determine the number of DDI alerts, time saved, and time invested after suppressing clinically irrelevant alerts and adding clinical-decision support to relevant alerts. METHODS The most frequently occurring DDIs were evaluated for clinical relevance by a multidisciplinary expert panel. Pharmacist evaluation of relevant DDIs was facilitated using computerized decision support systems (CDSS). During Phase 1, only CDSS-assisted DDI checking was implemented. During Phase 2, CDSS-assisted DDI checking remained in place, and clinically irrelevant DDIs were suppressed. In each phase, the number of alerts and duration of pharmacist DDI checking were compared to conventional DDI checking. In addition, the time invested to implement and configure the CDSS was compared to the time saved using CDSS-assisted DDI checking. RESULTS CDSS-assisted DDI checking resulted in a daily decrease of DDI checking alerts from 65 to 47 alerts in Phase 1 (P = .03) and from 73 to 33 alerts in Phase 2 (P = .003). DDI checking duration decreased from 15 to 11 minutes (P = .044) and from 15½ to 8½ minutes (P = .001) in Phases 1 and 2, respectively. Almost 298 of the 392 hours required for implementation were invested by pharmacists. An annual timesaving of 30 hours yielded a return on investment of 9.8 years. CONCLUSIONS CDSS-assisted DDI checking resulted in a 55% reduction of the number of alerts and a 45% reduction in time spent on DDI checking, yielding a return on investment of almost 10 years. Our approach can be used to refine other drug safety checking modules, increasing the efficiency of checking for drug safety without the need to add more staff pharmacists.