Drug-drug interactions (DDIs) frequently trigger adverse drug events or reduced efficacy. Most DDI alerts, however, are overridden because of irrelevance for the specific patient. Basic DDI clinical decision support (CDS) systems offer limited possibilities for decreasing the number of irrelevant DDI alerts without missing relevant ones. Computerized decision tree rules were designed to context-dependently suppress irrelevant DDI alerts. A crossover study was performed to compare the clinical utility of contextualized and basic DDI management in hospitalized patients. First, a basic DDI-CDS system was used in clinical practice while contextualized DDI alerts were collected in the background. Next, this process was reversed. All medication orders (MOs) from hospitalized patients with at least one DDI alert were included. The following outcome measures were used to assess clinical utility: positive predictive value (PPV), negative predictive value (NPV), number of pharmacy interventions (PIs)/1,000 MOs, and the median time spent on DDI management/1,000 MOs. During the basic DDI management phase 1,919 MOs/day were included, triggering 220 DDI alerts/1,000 MOs; showing 57 basic DDI alerts/1,000 MOs to pharmacy staff; PPV was 2.8% with 1.6 PIs/1,000 MOs costing 37.2 minutes/1,000 MOs. No DDIs were missed by the contextualized CDS system (NPV 100%). During the contextualized DDI management phase 1,853 MOs/day were included, triggering 244 basic DDI alerts/1,000 MOs, showing 9.6 contextualized DDIs/1,000 MOs to pharmacy staff; PPV was 41.4% (P < 0.01), with 4.0 PIs/1,000 MOs (P < 0.01) and 13.7 minutes/1,000 MOs. The clinical utility of contextualized DDI management exceeds that of basic DDI management.