Adult immunization rates are consistently suboptimal, exacting significant human and financial burden of preventable disease. Practice-level interventions to improve immunization rates have produced mixed results. The context of change critically affects implementation of evidence-based interventions. We conducted a randomized controlled cluster trial of the 4 Pillars Practice Transformation Program to increase adult vaccination rates in primary care practices and used qualitative methods to test intervention effects and understand practice characteristics associated with implementation success. We conducted qualitative interviews with staff from 14 practices to assess implementation experiences. Thematic analysis of data pointed to the importance of quality improvement history, communication and practice leadership, Immunization Champion leadership effectiveness, and organizational flexibility. Practices were scored on these characteristics and grouped into four types: Low Implementers, Medium Implementers, High Implementers, and Public/University Practices. Intervention uptake and immunization rate changes were compared, and a significant increase in influenza vaccination rates (3.9 percentage points [PPs]; p = .038) was observed for High Implementers only. Significant increases in Tdap vaccination rates were observed for High Implementers (9.3 PP; p = 0.006) and the Public/University groups (6.5 PP; p = 0.012), but not other groups. Practice characteristics may be critical factors in predicting intervention success.