BackgroundInter-organisational collaboration is increasingly prominent within contemporary healthcare systems. A range of collaboration types such as alliances, networks, and mergers have been proposed as a means to turnaround organisations, by reducing duplication of effort, and enabling resource sharing, greater influence, and novel innovations. However, in practice, due to the complexity of the process, such efforts are often rife with difficulty. Notable contributions have sought to make sense of this area, however further understanding is needed in order to gain a better understanding of why some inter-organisational collaborations work when others do not, to be able to more effectively implement collaborations in the future.MethodsRealist review methodology was used, combining systematically searched papers and purposively searched ‘middle-range’ theories. The systematic review encompassed searches for reviews, commentaries, opinion pieces and case studies on HMIC, Medline, PsychINFO, and Social Policy and Practice databases and further searches were conducted using Google Scholar. Data were extracted from included studies according to relevance to the realist review.ResultsThirty-eight systematically-identified studies were included, in addition to twelve purposively-identified papers, informing the development of programme theories of how, why, and when partnerships in healthcare work. The findings led to the proposal of programme theories formulated as context-mechanism-outcome configurations, which outline what outcomes may be expected when partnerships are attempted in differing contexts. We found that it was essential to consider mechanisms underlying partnership functioning, such as building trust and faith in the collaboration, in a context of strong initial trust, to enable maximal synergy and thus collaborative performance.ConclusionAs the first realist review of inter-organisational collaborations in healthcare as an intervention for improvement, this review provides actionable evidence for policymakers and implementers, enhancing understanding of mechanisms underlying the functioning and performing of inter-organisational collaborations, as well as configuring context and entry point to aid success. Next steps in this research will test the results against further case studies and primary data to produce a further refined theory. Review registrationThis review is registered at PROSPERO with ID CRD42019149009.