Individuals with dementia or mild cognitive impairment frequently have multiple chronic conditions (defined as ≥2 chronic medical conditions) and take multiple medications, increasing their risk for adverse outcomes. Deprescribing (reducing or stopping medications for which potential harms outweigh potential benefits) may decrease their risk of adverse outcomes. To examine the effectiveness of increasing patient and clinician awareness about the potential to deprescribe unnecessary or risky medications among patients with dementia or mild cognitive impairment. This pragmatic, patient-centered, 12-month cluster randomized clinical trial was conducted from April 1, 2019, to March 31, 2020, at 18 primary care clinics in a not-for-profit integrated health care delivery system. The study included 3012 adults aged 65 years or older with dementia or mild cognitive impairment who had 1 or more additional chronic medical conditions and were taking 5 or more long-term medications. An educational brochure and a questionnaire on attitudes toward deprescribing were mailed to patients prior to a primary care visit, clinicians were notified about the mailing, and deprescribing tip sheets were distributed to clinicians at monthly clinic meetings. The number of prescribed long-term medications and the percentage of individuals prescribed 1 or more potentially inappropriate medications (PIMs). Analysis was performed on an intention-to-treat basis. This study comprised 1433 individuals (806 women 56.2%; mean SD age, 80.1 7.2 years) in 9 intervention clinics and 1579 individuals (874 women 55.4%; mean SD age, 79.9 7.5 years) in 9 control clinics who met the eligibility criteria. At baseline, both groups were prescribed a similar mean (SD) number of long-term medications (7.0 2.1 in the intervention group and 7.0 2.2 in the control group), and a similar proportion of individuals in both groups were taking 1 or more PIMs (437 of 1433 individuals 30.5% in the intervention group and 467 of 1579 individuals 29.6% in the control group). At 6 months, the adjusted mean number of long-term medications was similar in the intervention and control groups (6.4 95% CI, 6.3-6.5 vs 6.5 95% CI, 6.4-6.6; P = .14). The estimated percentages of patients in the intervention and control groups taking 1 or more PIMs were similar (17.8% 95% CI, 15.4%-20.5% vs 20.9% 95% CI, 18.4%-23.6%; P = .08). In preplanned subgroup analyses, adjusted differences between the intervention and control groups were -0.16 (95% CI, -0.34 to 0.01) for individuals prescribed 7 or more long-term medications at baseline (n = 1434) and -0.03 (95% CI, -0.20 to 0.13) for those prescribed 5 to 6 medications (n = 1578) (P = .28 for interaction; P = .19 for subgroup interaction for PIMs). This large-scale educational deprescribing intervention for older adults with cognitive impairment taking 5 or more long-term medications and their primary care clinicians demonstrated small effect sizes and did not significantly reduce the number of long-term medications and PIMs. Such interventions should target older adults taking relatively more medications. ClinicalTrials.gov Identifier: NCT03984396.