This research describes a medication safety framework for primary care office-based practices and evaluates how offices manage the medication use process within this framework. The conceptual model supporting the safety framework integrates structure, process, and outcome quality concepts relevant to medication safety. Medication safety domains were identified through a review of published literature; the Agency for Healthcare Research and Quality (AHRQ) patient safety agenda; research portfolios, reports, guidelines, and standards from private and public organizations; and an onsite evaluation of the medication use process in two primary care offices. Domains identified include the medication use process, technology and safety, the office environment, error management, workplace conditions, safety education. safety perceptions, and patient education. Based upon these domains, a 154-item written survey was developed to assess medication safety in office practice. It was administered to 31 primary care office-based practices in the Nebraska and Iowa region, using the interviewer-assisted technique. A direct observation study, onsite technology readiness survey, and accessibility of drug information sources were conducted concurrently. Results provide evidence that a medication safety framework is lacking in office-based practice. Suboptimal—and sometimes unacceptable—practices related to medication safety in primary care offices are identified and described. Results may be used to describe the medication safety framework and to identify best practices for office-based medication safety.