States and the World Health Organization (WHO), an international organization that is mandated to respect the sovereignty of its member states, are still the leading actors in global health. This paper explores how this discrepancy inhibits the ability of global health partnerships to implement programmes in conflict-affected areas that are under the de facto control of rebel organizations. We concentrate on a single crucial case, the polio outbreak in Syria in 2013, analysing a variety of qualitative data—twenty semi-structured interviews with key actors, official documents, and media reports—in order to investigate the events that preceded and followed this event. The WHO’s mandate to respect the Syrian government’s sovereignty inhibited its ability to prevent, identify and contain the outbreak because the Assad regime refused it permission to operate in rebel-controlled areas. The polio outbreak was identified and contained by organizations operating outside the United Nations (UN) system that disregarded the Syrian government’s sovereignty claims and cooperated with the militants. Thus, we identify a serious problem with so-called global health partnerships in which nation states and international organizations remain key actors. Such initiatives function well in situations where there is a capable state that is concerned with the welfare of its citizens and has exclusivity of jurisdiction over its territory. But they can encounter difficulties in areas where rebels challenge the state’s sovereignty. Although the response to the Syrian polio outbreak was ultimately effective, it was reactive, ad hoc, slow and relied on personnel who had little experience. Global health partnerships would be more effective in conflict-affected areas if they put in place proactive and institutionalized plans to implement their programmes in regions outside government control.