Complex medication regimens pose self-management challenges, particularly among populations with low levels of health literacy. To test medication management tools delivered through a commercial electronic health record (EHR) with and without a nurse-led education intervention. 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. 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. 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. 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). 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. ClinicalTrials.gov identifier: NCT01578577.