Purpose: Drug-drug interactions (DDIs) may cause adverse outcomes in patients admitted to the Intensive Care Unit (ICU). Computerized decision support systems (CDSSs) may help prevent DDIs by timely showing relevant warning alerts, but knowledge on which DDIs are clinically relevant in the ICU setting is limited. Therefore, the purpose of this study was to identify DDIs relevant for the ICU. Materials and methods: We conducted a modified Delphi procedure with a Dutch multidisciplinary expert panel consisting of intensivists and hospital pharmacists to assess the clinical relevance of DDIs for the ICU. The procedure consisted of two rounds, each included a questionnaire followed by a live consensus meeting. Results: In total the clinical relevance of 148 DDIs was assessed, of which agreement regarding the relevance was reached for 139 DDIs (94%). Of these 139 DDIs, 53 (38%) were considered not clinically relevant for the ICU setting. Conclusions: A list of clinically relevant DDIs for the ICU setting was established on a national level. The clinical value of CDSSs for medication safety could be improved by focusing on the identified clinically relevant DDIs, thereby avoiding alert fatigue.