ABSTRACT: Importance:Complex medication regimens pose self-management challenges, particularly among populations with low levels of health literacy. Objective:To test medication management tools delivered through a commercial electronic health record (EHR) with and without a nurse-led education intervention. Design, Setting, and Participants:This 3-group cluster randomized clinical trial was performed in community health centers in Chicago, Illinois. Participants included 794 patients with hypertension who self-reported using 3 or more medications concurrently (for any purpose). Data were collected from April 30, 2012, through February 29, 2016, and analyzed by intention to treat. Interventions:Clinics were randomly assigned to to groups: electronic health record-based medication management tools (medication review sheets at visit check-in, lay medication information sheets printed after visits; EHR-alone group), EHR-based tools plus nurse-led medication management support (EHR plus education group), or usual care. Main Outcomes and Measures:Outcomes at 12 months included systolic blood pressure (primary outcome), medication reconciliation, knowledge of drug indications, understanding of medication instructions and dosing, and self-reported medication adherence. Medication outcomes were assessed for all hypertension prescriptions, all prescriptions to treat chronic disease, and all medications. Results:Among the 794 participants (68.6% women; mean [SD] age, 52.7 [9.6] years), systolic blood pressure at 12 months was greater in the EHR-alone group compared with the usual care group by 3.6 mm Hg (95% CI, 0.3 to 6.9 mm Hg). Systolic blood pressure in the EHR plus education group was not significantly lower compared with the usual care group (difference, -2.0 mm Hg; 95% CI, -5.2 to 1.3 mm Hg) but was lower compared with the EHR-alone group (-5.6 mm Hg; 95% CI, -8.8 to -2.4 mm Hg). At 12 months, hypertension medication reconciliation was improved in the EHR-alone group (adjusted odds ratio [OR], 1.8; 95% CI, 1.1 to 2.9) and the EHR plus education group (adjusted odds ratio [OR], 2.0; 95% CI, 1.3 to 3.3) compared with usual care. Understanding of medication instructions and dosing was greater in the EHR plus education group than the usual care group for hypertension medications (OR, 2.3; 95% CI, 1.1 to 4.8) and all medications combined (OR, 1.7; 95% CI, 1.0 to 2.8). Compared with usual care, the EHR tools alone and EHR plus education interventions did not improve hypertension medication adherence (OR, 0.9; 95% CI, 0.6-1.4 for both) or knowledge of chronic drug indications (OR for EHR tools alone, 1.0 [95% CI, 0.6 to 1.5] and OR for EHR plus education, 1.1 [95% CI, 0.7-1.7]). Conclusions and Relevance:The study found that EHR tools in isolation improved medication reconciliation but worsened blood pressure. Combining these tools with nurse-led support suggested improved understanding of medication instructions and dosing but did not lower blood pressure compared with usual care. Trial Registration:ClinicalTrials.gov identifier: NCT01578577.