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The open ocean beyond national jurisdiction covers nearly half of Earth’s surface and is largely unexplored. It is also an emerging frontier for new types of human activity. Understanding how new activities interact with high seas ecosystems is critical for our management of this other half of Earth. Using The Ocean Cleanup (TOC) as a model, we demonstrate why it is important to account for uncertainty when assessing and evaluating impacts of novel high seas activities on marine ecosystems. TOC’s aim is to remove plastic from the ocean surface by collecting it with large nets. However, this approach also results in the collection of surface marine life (neuston) as by-catch. Using an interdisciplinary approach, we explore the social-ecological implications of this activity. We use population models to quantify potential impacts on the surface ecosystem; we determine the links between these ecosystems and society through an ecosystem services approach; and we review the governance setting relevant to the management of activities on the high seas. We show that the impact of ocean surface plastic removal largely depends on neuston life histories, and ranges from potentially mild to severe. We identify broader social-ecological implications that could be felt by stakeholders both beyond and within national jurisdiction. The legal framework applicable to TOC’s activities is insufficiently specific to address both the ecological and social uncertainty we describe, demonstrating the urgent need for detailed rules and procedures on environmental impact assessment and strategic environmental assessment to be adopted under the new International Agreement on the conservation and sustainable use of marine biological diversity of areas beyond national jurisdiction which is currently being negotiated.