OBJECTIVES: Electronic medical record (EMR) based clinical decision support system (CDSS) have been used to improve personalized medication safety. However, there were no studies to evaluating cost-effectiveness and cost-benefit of advanced medication safety-related CDSS in Korea. The objective was to evaluate the cost-effectiveness and cost-benefit of advanced medication safety-related CDSS on reduction of adverse drug events (ADEs) in Korea. METHODS: We conducted cost-effectiveness analysis (CEA) from the perspective of the hospital and cost-benefit analysis (CBA) from the societal perspective comparing before (Nov.2011~Jan.2015) and after (Nov.2015~Jan.2016) the adoption of the CDSS. The costs included the system input costs and costs of additional diagnostic lab test of advanced CDSS. Effectiveness outcome was the number of averted ADEs. Direct medical and non-medical costs and indirect benefits of averted ADEs were analyzed. The outcome measures were the incremental cost-effectiveness ratio (ICER) for the CEA and the benefit-to-cost ratio (BCR) and the net-benefit for the CBA. RESULTS: The system input costs were about $168,000. It was estimated that the advanced CDSS averted 26 ADEs. Total benefits of the averted ADEs were about $281,000. The ICER was about $6,573 per averted adverse drug event, the BCR was 1.81 and the net-Benefit was about $125,000. CONCLUSIONS:  Implementing advanced medication safety-related CDSS appeared to be a cost-beneficial strategy. More studies are needed to assess the effectiveness and benefits on reduction of adverse events and other medication safety include medication errors for CDSS.