Drug-drug interactions (DDI) can be harmful. This study examined frequency of potential DDI (pDDI) and clinically relevant DDI (cDDI) in three hospitals both before and after implementation of an electronic medication management (EMM) system, without accompanying decision support alerts. The frequency of pDDI and cDDI orders did not differ between timeframes, although the likelihood of both drugs being co-administered was lower post-EMM implementation. Only one-quarter of pDDI were clinically relevant, and actual harm was less than 1% in both timeframes and was primary mild. Given the low prevalence of actual harm and the decreased likelihood of co-administration of drugs even without alerts, caution should be used when implementing DDI alerts so as not to introduce alert fatigue.