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Key Points Question Does providing clinical decision support during an acute care hospitalization improve deprescribing of potentially inappropriate medications and 30-day postdischarge adverse drug events (ADEs) in older adults? Findings This cluster randomized multicenter trial of 5698 hospitalized participants found that providing electronically generated deprescribing reports did not have a significant impact on ADEs within 30 days despite increased deprescribing at discharge. Meaning The findings of this randomized clinical trial indicate that clinical decision support during hospitalization improves deprescribing but has little impact on medication harms in the short term., Importance Scalable deprescribing interventions may reduce polypharmacy and the use of potentially inappropriate medications (PIMs); however, few studies have been large enough to evaluate the impact that deprescribing may have on adverse drug events (ADEs). Objective To evaluate the effect of an electronic deprescribing decision support tool on ADEs after hospital discharge among older adults with polypharmacy. Design, Setting, and Participants This was a cluster randomized clinical trial of older (≥65 years) hospitalized patients with an expected survival of more than 3 months who were admitted to 1 of 11 acute care hospitals in Canada from August 22, 2017, to January 13, 2020. At admission, participants were taking 5 or more medications per day. Data analyses were performed from January 3, 2021, to September 23, 2021. Interventions Personalized reports of deprescribing opportunities generated by MedSafer software to address usual home medications and measures of prognosis and frailty. Deprescribing reports provided to the treating team were compared with usual care (medication reconciliation). Main Outcomes and Measures The primary outcome was a reduction of ADEs within the first 30 days postdischarge (including adverse drug withdrawal events) captured through structured telephone surveys and adjudicated blinded to intervention status. Secondary outcomes were the proportion of patients with 1 or more PIMs deprescribed at discharge and the proportion of patients with an adverse drug withdrawal event (ADWE). Results A total of 5698 participants (median [range] age, 78 [72-85] years; 2858 [50.2%] women; race and ethnicity data were not collected) were enrolled in 3 clusters and were adjudicated for the primary outcome (control, 3204; intervention, 2494). Despite cluster randomization, there were group imbalances, eg, the participants in the intervention arm were older and had more PIMS prescribed at baseline. After hospital discharge, 4989 (87.6%) participants completed an ADE interview. There was no significant difference in ADEs within 30 days of discharge (138 [5.0%] of 2742 control vs 111 [4.9%] of 2247 intervention participants; adjusted risk difference [aRD] −0.8%; 95% CI, −2.9% to 1.3%). Deprescribing increased from 795 (29.8%) of 2667 control to 1249 (55.4%) of 2256 intervention participants [aRD, 22.2%; 95% CI, 16.9% to 27.4%]. There was no difference in ADWEs between groups. Several post hoc sensitivity analyses, including the use of a nonparametric test to address the low cluster number, group imbalances, and potential biases, did not alter study conclusions. Conclusions and Relevance This cluster randomized clinical trial showed that providing deprescribing clinical decision support during acute hospitalization had no demonstrable impact on ADEs, although the intervention was safe and led to improvements in deprescribing. Trial Registration ClinicalTrials.gov Identifier: NCT03272607, This randomized clinical trial examines the impact of electronic decision support on postdischarge adverse drug events and deprescribing among hospitalized patients 65 years or older at 11 hospitals in Canada.