Reducing medication errors is a fundamental patient safety goal; however, few improvement interventions have been evaluated in primary care settings. The Medication Safety in Primary Care Practice project was designed to test the impact of a multimethod quality improvement intervention on 5 categories of preventable prescribing and monitoring errors in 20 Practice Partner Research Network (PPRNet) practices. PPRNet is a primary care practice-based research network among users of a common electronic health record (EHR). The intervention was associated with significant improvements in avoidance of potentially inappropriate therapy, potential drug-disease interactions, and monitoring of potential adverse events over 2 years. Avoidance of potentially inappropriate dosages and drug-drug interactions did not change over time. Practices implemented a variety of medication safety strategies that may be relevant to other primary care audiences, including use of EHR-based audit and feedback reports, medication reconciliation, decision-support tools, and refill protocols.