The habitat and biota most affected by ultra-deep oil spills in the Gulf of Mexico (GoM) will necessarily be in the deep-pelagic domain. This domain represents ~91% of the GoM’s volume and almost certainly contains the majority of its metazoan inhabitants. Ultra-deep oil spills may or may not reach the surface or the seafloor but will occur entirely within the deepwater column domain at some point and likely for the longest duration. Recent research has shown the deep-pelagic GoM to be extremely rich in biodiversity, both taxonomic and functional. Indeed, the GoM is one of the four “hyperdiverse” midwater ecosystems in the World Ocean. This biodiversity is functionally important. For example, well over half (58%) of all fish species known to exist in the GoM spend all or part of their lives in the oceanic domain. Recent research has also shown the deep-pelagic GoM to be highly connected vertically, as well as horizontally (onshore-offshore). This vertical connectivity provides an increasingly valued ecosystem service in the form of atmospheric carbon sequestration via the “biological pump.” In this chapter, we summarize the GoM deep-pelagic nekton (fishes, macrocrustaceans, and cephalopods) that have been, and would be, affected by ultra-deep oil spills. We also discuss key aspects of distribution and behavior (e.g., vertical migration). These behaviors and distributions are key elements of ecosystem assessments before and after oil spills. For example, some deep-pelagic taxa show affinities for oceanic rim habitats (i.e., continental slopes), where ultra-deep drilling is most intense. Lastly, we summarize what is known about hydrocarbon contamination in the deep-pelagic biota and its possible ecosystem consequences.