The Patient Protection and Affordable Care Act, which promoted quality of care, started the transformation of healthcare systems in the United States. The purpose of this qualitative multiple case study was to explore clinical practice innovation strategies used by hospital middle managers to improve quality of care and profitability. Pettigrew's theory was the conceptual framework for this study. Participants were 8 middle managers from 2 high-performing hospitals in the southwestern region of the United States. Data were collected from semistructured interviews, personal notes, and review of the hospital's publicly reported documents and literature. Member checking and methodological triangulation increased the credibility, validity, reliability, and trustworthiness of the study findings. Content and thematic data analysis provided the basis for coding the findings. Data analysis resulted in the emergence of 4 themes: organizational culture, leadership, systematic approach to management by objectives, and staff engagement. The findings showed the interactions among internal context, content, and process constructs of Pettigrew's theory as relevant to clinical practice innovation strategies for improving the quality of care and organizational profitability. The implications for positive social change include the potential for hospital middle managers to implement innovative strategies to improve patients' quality of care and save lives and the overall health and wellness of individuals in the communities they serve.