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Background Because of an expected shrinking supply of medical doctors for hospitalist posts, an increased emphasis on efficiency and continuity of care, and the standardization of many medical procedures, the role of hospitalist is increasingly allocated to physician assistants (PAs). PAs are nonphysician clinicians with medical tasks. This study aims to evaluate the effects of substitution of hospital ward care to PAs. Methods/design In a multicenter matched controlled study, the traditional model in which the role of hospitalist is taken solely by MDs (MD model) is compared with a mixed model in which a PA functions as a hospitalist, contingent with MDs (PA/MD model). Twenty intervention and twenty control wards are included across The Netherlands, from a range of medical specialisms. Primary outcome measure is patients' length of hospital stay. Secondary outcomes include indicators for quality of hospital ward care, patients experiences with medical ward care, patients health-related quality of life, and healthcare providers' experiences. An economic evaluation is conducted to assess the cost implications and potential efficiency of the PA/MD model. For most measures, data is collected from medical records or questionnaires in samples of 115 patients per hospital ward. Semi-structured interviews with healthcare professionals are conducted to identify determinants of efficiency, quality and continuity of care and barriers and facilitators for the implementation of PAs in the role of hospitalist. Discussion Findings from this study will help to further define the role of nonphysician clinicians and provides possible key components for the implementation of PAs in hospital ward care. Like in many studies of organizational change, random allocation to study arms is not feasible, which implies an increased risk for confounding. A major challenge is to deal with the heterogeneity of patients and hospital departments. [ABSTRACT FROM AUTHOR]