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BackgroundLeadership is a key component for infection prevention and control and plays an important role in the implementation of guidelines on healthcare-associated infections. A body of literature exists on healthcare workers’ perspectives on implementing these types of guidelines; however, there is a paucity of data on the leadership perspectives on implementation. This study aims to contribute to the evidence base of leadership perspectives.ObjectiveTo explore the implementation of National Clinical Guidelines pertaining to methicillin-resistant Staphylococcus aureus and Clostridium difficile from the leadership angle.SettingHealthcare organisations.ParticipantsClinical and non-clinical leaders.DesignThis research used a mixed-methods approach comprising qualitative individual interviews (n=16) and quantitative surveys (n=51) underpinned by the integrated Promoting Action on Research Implementation in Health Services framework.ResultsLeaders recognise the value and innovation of guidelines to support clinical practice. However, they describe barriers to implementation that prevent the full uptake of guidelines, for example, guidelines may present an ideological approach to care which differs from the contextual reality of clinical practice where resources and time are not always available.ConclusionThis research highlighted that guidelines are complex interventions in complex organisations, perhaps leadership could help overcome the challenges posed by this complexity. Leadership may allow a systematic approach to all aspects of implementation despite the variety of challenges faced at different stages of implementation and sustainability of uptake of guidelines over time.