ABSTRACT Palaeogene South American faunas include enigmatic ungulates that cannot be classified unequivocally within any of the main South American (SA) Native Ungulates clades (Litopterna, Notoungulata, Astrapotheria, Pyrotheria and Xenungulata) because they retain plesiomorphic features, resembling Laurasian ‘archaic ungulates’ traditionally classified within the order ‘Condylarthra’. Most SA ‘condylarths’ are known by partial dental series and isolated teeth and unassociated postcranial remains, hampering comparisons with better-known ungulates. Here, we describe a nearly complete skull and associated mandible of an SA ‘condylarth’, Talquinodus puertai gen. et sp. nov., preserving most of the dentition and basicranium, derived from middle Eocene rocks of the Sarmiento Formation at Central Patagonia. Talquinodus shows a combination of plesiomorphic traits (complete dentition with bunolophodont cheek teeth, ring like ectotympanic, retention of stapedial system, etc.), combined with some autapomorphies, as the reduction of the m3 talonid. Our phylogenetic analyses support consistently that Talquinodus belongs to the SA radiation of Euungulata along with Litopterna, Notoungulata and Astrapotheria. However, the internal relationships could not be resolved unambiguously: Talquinodus could be a didolodontid related to the origin of Litopterna, or could be part of a separate radiation of South American archaic ungulates, along Depaulacoutoia, Lamegoia and Escribania, with no descendants in post-Eocene faunas.