South America had an endemic mammalian fauna for much of the Cenozoic, largely evolved during its long isolation. The predator guild was mainly occupied by metatherians (Sparassodonta), as well as large terrestrial birds (Phorusrhacidae), agile terrestrial crocodiles (Sebecidae), and giant snakes (Madtsoiidae). Sparassodonta was a diverse clade, recorded from the Paleocene to the Middle Pliocene, with its acme in the late Early Miocene (Santacrucian Age). In this chapter, we review the paleoecology of the sparassodonts known from the Santa Cruz Formation and include new results obtained by geometric morphometric analyses. The Santa Cruz Formation contains 11 sparassodont species: six Hathliacynidae (Acyon tricuspidatus, Cladosictis patagonica, Sipalocyon gracilis, Sipalocyon obusta, Pseudonotictis pusillus, Perathereutes pungens) and five Borhyaenoidea (Prothylacynus patagonicus, Lycopsis torresi, and three Borhyaenidae, Borhyaena tuberata, Acrocyon sectorius, and Arctodictis munizi). These sparassodonts were mainly hypercarnivores exhibiting different locomotor abilities (from scansorial to terrestrial), and a wide range of body masses (from 1 kg to more than 50 kg). The reconstruction of the Santacrucian predator guild suggests that there was good ecological separation within the sparassodonts, determined by particular combinations of body size, locomotion, and diet. The diversity of sparassodonts recorded in the Santa Cruz Formation (11 species) and in the Estancia La Costa Member (seven species), is similar to that observed in present and past placental hypercarnivore communities.