Emerging evidence that meaningful relationships with knowledge users are a key predictor of research use has led to promotion of partnership approaches to health research. However, little is known about health system experiences of collaborations with university-based researchers, particularly with research partnerships in the area of health system design and health service organization. The purpose of the study was to explore the experience and perspectives of senior health managers in health service organizations, with health organization-university research partnerships.In-depth, semi-structured interviews (n = 25) were conducted with senior health personnel across Canada to explore their perspectives on health system research; experiences with health organization-university research partnerships; challenges to partnership research; and suggested actions for improving engagement with knowledge users and promoting research utilization. Participants, recruited from organizations with regional responsibilities, were responsible for system-wide planning and support functions.Research is often experienced as unhelpful or irrelevant to decision-making by many within the system. Research, quality improvement (QI) and evaluation are often viewed as separate activities and coordinated by different responsibility areas. Perspectives of senior managers on barriers to partnership differed from those identified in the literature: organizational stress and restructuring, and limitations in readiness of researchers to work in the fast-paced healthcare environment, were identified as major barriers. Although the need for strong executive leadership was emphasized, "multi-system action" is needed for effective partnerships.Common approaches to research and knowledge translation are often not appropriate for addressing issues of health service design and health services organization. Nor is the research community providing expertise to many important activities that the healthcare system is taking to improve health services. A radical rethinking of how we prepare health service researchers; position research within the health system; and fund research activities and infrastructure is needed if the potential benefits of research are to be achieved. Lack of response to health system needs may contribute to research and 'evidence-informed' practice being further marginalized from healthcare operations. Interventions to address barriers must respond to the perspectives and experience of health leadership.