BackgroundASSET (Health System Strengthening in Sub-Saharan Africa) is a health system strengthening (HSS) programme that aims to develop and evaluate effective and sustainable solutions that support high-quality care that involve eight work packages across four sub-Saharan African countries. Here we present the protocol for the implementation science (IS) theme within ASSET that aims to (1) understand what HSS interventions work, for whom and how; and (2) how implementation science methodologies can be adapted to improve the design and evaluation of HSS interventions within resource-poor contexts.MethodsPre-implementation phaseThe IS theme, jointly with ASSET work-packages, applies IS determinant frameworks to identify factors that influence the effectiveness of delivering evidence-informed care. Determinants are used to select a set of HSS interventions for further evaluation, where work packages also theorise selective mechanisms to achieve the expected outcomes.Piloting phase and rolling implementation phaseWork-packages pilot the HSS interventions. An iterative process then begins involving evaluation, refection and adaptation. Throughout this phase, IS determinant frameworks are applied to monitor and identify barriers and enablers to implementation in a series of workshops, surveys and interviews. Selective mechanisms of action are also investigated. In a final workshop, ASSET teams come together, to reflect and explore the utility of the selected IS methods and provide suggestions for future use.Structured templates are used to organise and analyse common and heterogeneous patterns across work-packages. Qualitative data are analysed using thematic analysis and quantitative data is analysed using means and proportions.ConclusionsWe use a novel combination of implementation science methods at a programmatic level to facilitate comparisons of determinants and mechanisms that influence the effectiveness of HSS interventions in achieving implementation outcomes across different contexts. The study will also contribute conceptual development and clarification at the underdeveloped interface of implementation science, HSS and global health.Strengths and limitations of this studyThe purpose of this protocol paper is to describe the methodology for the implementation science theme within ASSET (ASSET-ImplementER).The overall aim of the ASSET-ImplementER theme is to advance our understanding of how to design and evaluate HSS interventions using a systems level approach informed by implementation science, across different health systems and contexts.This is one of the first large-scale implementation research programmes for health system strengthening in Sub-Saharan Africa that spanning three care platforms (primary care for the integrated treatment of chronic conditions in adults, maternal and newborn care, surgical care), involving eight work packages in four sub-Saharan African countries that aims to apply robust, implementation science and other theory-informed approaches to understand what works for whom and how. Equally as important, we aim to improve implementation science methodologies to design and evaluate HSS interventions within LMIC settings.Although our programme is theory-informed through the use of ToC workshops andimplementation science determinant frameworks, we have not used implementation science theories or other middle-range theories to guide the design and evaluate of ASSET as a programme. This is a pragmatic approach given many of the work-packages teams were unfamiliar with implementation science methods at the time of ASSET set-up.To mitigate the effects of this approach to our research, we work with the different work packages throughout the different phases of research, to theorise and conceptualise how the selected determinants interact with mechanisms introduced by the selected HSS on implementation outcomes.Although there are limitations to our approach, we expect to begin advance our understanding of what HSS work for whom, and how. It is also hoped that we will start to address the issues in understanding the complexity surrounding how to effectively strengthen health systems in resource-poor contexts within LMICs.