STUDY OBJECTIVES To enhance physician and patient awareness of polypharmacy; to decrease the risks, drug costs, and waste resulting from polypharmacy; and to make the business case for reducing misuse, overuse, and underuse of drugs by reducing polypharmacy. DESIGN Longitudinal, time series cohort. SETTING Outpatient, managed care, integrated delivery system. PATIENTS A total of 195,971 patients who received health care from the Henry Ford Medical Group and had health insurance coverage from the Health Alliance Plan. MEASUREMENTS AND MAIN RESULTS Two identical interventions separated by 1 year were conducted in patients at high risk of harm from polypharmacy based on five categories of high-risk drug combinations (referred to as polypharmacy events). Six months of pharmacy claims data were reviewed before and after each intervention to identify these patients. The intervention program consisted of clinical pharmacists performing drug therapy reviews, educating physicians and patients about drug safety and polypharmacy, and working with physicians and patients to correct polypharmacy problems. Prescription cost/member/month, number of prescriptions/member/month, and rates of polypharmacy events/1000 members were measured before and after each of the two interventions. After the first intervention, the overall rate of polypharmacy events decreased from 29.01 to 9.43/1000 patients (67.5% reduction). The number of prescriptions/member/month decreased from 4.6 to 2.2 (52.2% reduction), prescription cost/member/month decreased from $222 to $113 (49.1% reduction), and overall institution drug cost was reduced by $4.8 million. Six months after the second intervention, the overall rate of polypharmacy events was reduced from 27.99 to 17.07/1000 (39% reduction), the number of prescriptions/member/month decreased from 4.5 to 4.0 (11.1% reduction), and prescription cost/member/month decreased from $264 to $239 (9.5% reduction). Overall institution drug costs were reduced by $1.3 million. Sustained effects were seen for all measures of polypharmacy (p=0.001). CONCLUSIONS These interventions reduced drug costs and numbers of prescriptions in a managed care cohort of patients at high risk for adverse drug events due to polypharmacy. By providing clinical information, decision support, patient self-management support, and care delivery redesign some of the problems resulting from polypharmacy can be solved.