PURPOSE: The methods and costs to enroll small primary care practices in large, regional quality improvement initiatives are unknown. We describe the recruitment approach, cost, and resources required to recruit and enroll 500 practices in the Northwest and Midwest regional cooperatives participating in the Agency for Healthcare Research and Quality (AHRQ)-funded initiative, EvidenceNOW: Advancing Heart Health in Primary Care. METHODS: The project management team of each cooperative tracked data on recruitment methods used for identifying and connecting with practices. We developed a cost-of-recruitment template and used it to record personnel time and associated costs of travel and communication materials. RESULTS: A total of 3,669 practices were contacted during the 14- to 18-month recruitment period, resulting in 484 enrolled practices across the 6 states served by the 2 cooperatives. The average number of interactions per enrolled practice was 7, with a total of 29,100 hours and a total cost of $2.675 million, or $5,529 per enrolled practice. Prior partnerships predicted recruiting almost 1 in 3 of these practices as contrasted to 1 in 20 practices without a previous relationship or warm hand-off. CONCLUSIONS: Recruitment of practices for large-scale practice quality improvement transformation initiatives is difficult and costly. The cost of recruiting practices without existing partnerships is expensive, costing 7 times more than reaching out to familiar practices. Investigators initiating and studying practice quality improvement initiatives should budget adequate funds to support high-touch recruitment strategies, including building trusted relationships over a long time frame, for a year or more.