Objectives Data on the clinical impact of a drug information service (DIS) on patient care are still insufficient. By analysing clinical actions following DIS response to enquiries, we studied the impact of a DIS on clinical decision making, specifically concerning drug–drug interactions (DDI). Methods A prospective study, November 2008 to December 2009, identified physicians’ enquiries on DDIs to a university hospital pharmacy DIS. Written response was analysed for reason of enquiry, number and severity of DDI and recommended clinical actions. Enquirers were contacted by telephone and asked what clinical actions had been taken to manage DDI and if they were based on DIS response. Results Out of 149 enquiries on DDI, 113 were patient-specific, made by physicians, and the structured telephone interview was completed. 420 potential DDIs were identified: 85 requiring clinical action, 210 needing observation, 125 theoretical. The telephone interview revealed 232 clinical actions implemented to manage possible DDIs: 114 solely initiated following written DIS response, 118 for other reasons. Out of these 118, many were actually recommended by the DIS but had already been implemented as routine clinical actions during hospital stay like laboratory testing. Reason for enquiry was, in 71 cases preventive, in 18 cases a suspected DDI causing a clinical problem and in 24 cases general DDI-test based on a multidrug regimen. Conclusions The DIS has a direct impact on patient care. Response on DDI enquiries was translated in clinical actions to ensure safe drug therapy, and helps in answering clinical questions.