Background: The importance of contextual factors to the applicability and usefulness of primary studies and systematic reviews for policymakers, managers and practitioners has been recognised in recent amendments to the CONSORT Statement, and in tools and strategies to evaluate and promote the applicability of research in local settings. Low-income and middle-income countries are disproportionately affected by concerns about applicability, since most research evidence comes from high-income countries. Means to assist the end user to better appraise barriers and facilitators in their own contexts may be helpful and complementary to the efforts of researchers and reviewers. Objectives: To develop and test a conceptual framework to aid understanding of contextual heterogeneity on research applicability. Methods: A framework was developed through a consensus approach based on a review of the various perspectives to research generalisability, applicability and transferability. The usefulness of the framework for systematic reviews was then considered. Results: The context framework has the point of interaction between a provider and a patient at its centre, and the attributes of systems, populations and environments which affect the degree to which an individual might benefit or otherwise from a healthcare intervention as the relevant context. These act primarily through effects on access to and quality of the healthcare interaction. We offer explicit definitions for the components of the framework, and illustrate how it may be used with examples in a diverse range of clinical applications. Conclusions: The context of healthcare interventions and the potential interaction of myriad different factors is challenging. We believe our framework helps to simplify and clarify contextual considerations, thereby encouraging researchers and decision-makers to incorporate them in evaluating the applicability and relevance of research.