Practice facilitation is all about supporting quality improvement (QI) and assisting practices in matching with the best evidence. Strategies contributing to a facilitator’s efficacy are rarely investigated, especially in studies of this scale and complexity. Using data from EvidenceNOW, a massive QI program, researchers conducted a sequential mixed methods investigation. With the help of 162 facilitators employed by 7 regional cooperatives, 1,630 primary care practices, both large and small, could improve their operations and provide better patient care. Facilitators involved in at least 4 different practices were used for the primary statistical analyses. If at least 75% of the practices the facilitator worked with showed improvement from baseline to follow-up on aspirin use, blood pressure control, smoking cessation counseling (ABS), or practice change capacity (as measured by the Change Process Capability Questionnaire), the facilitator was considered more effective. When evaluating the effectiveness of facilitators, the threshold for failure was set at 50% of practices improving on these outcomes. They investigated observational and interview data using a crystallization and comparison method to determine tactics used by more effective facilitators. Compared to practices using less effective facilitators, those using more effective facilitators saw a 3.6% increase in the mean percentage of patients meeting the composite ABS measure (P<.001). The most effective facilitators used a combination of tactics to foster motivation, such as personalizing QI work and addressing resistance, guiding practices to think critically, and providing accountability to encourage change. It was impressive how well they articulated their processes. Conversely, ineffective facilitators rarely employed such techniques and provided broad descriptions of their activities. There was no difference between the most and least effective facilitators regarding their educational background, professional experience, or time spent on paperwork. Facilitation techniques that help to distinguish between good and bad facilitators have implications for better facilitator development and training, and they can help all facilitators support practice improvements more effectively.