South Africa is currently proclaiming a Marine Protected Area (MPA) in the Exclusive Economic Zone (EEZ) of its sub-Antarctic Prince Edward Islands. The objectives of the MPA are to: (1) contribute to a national and global representative system of MPAs; (2) serve as a scientific reference point to inform future management; (3) contribute to the recovery of the Patagonian toothfish (Dissostichus eleginoides); and (4) reduce the bird bycatch of the toothfish fishery, particularly of albatrosses and petrels. This study employs systematic conservation planning methods to delineate a MPA within the EEZ that will conserve biodiversity patterns and processes within sensible management boundaries, while minimizing conflict with the legal toothfish fishery. After collating all available distributional data on species, benthic habitats and ecosystem processes, we used C-Plan software to delineate a MPA with three management zones: four IUCN Category Ia reserves (13% of EEZ); two Conservation Zones (21% of EEZ); and three Category IV reserves (remainder of EEZ). Compromises between conservation target achievement and the area required by the MPA are apparent in the final reserve design. The proposed MPA boundaries are expected to change over time as new data become available and as impacts of climate change become more evident.