The family Isotemnidae, now considered paraphyletic by some, is composed of the most basal members of the suborder Toxodontia. They were moderate to large, plantigrade or semidigitigrade mammals, with features related to weight bearing. Several isolated postcranial remains from the Sapoan Fauna (early Eocene) have been referred to one of the earliest isotemnid genera, Isotemnus. This is the largest notoungulate genus found in the Sapoan Fauna, and isotemnid remains can be distinguished from those of similarly-sized notostylopids. Here, the anatomy of these remains is compared with those of later isotemnids, Thomashuxleya and Periphragnis. Isotemnus was one of the smallest isotemnids (around 50 kg, inferred from the astragalus) while Thomashuxleya and Periphragnis were four times larger (∼200 kg). Thomashuxleya and Periphragnis share features not present in other Eocene notoungulates such as Notohippidae or Notostylopidae, including: a distal humerus with a sharp, salient medial trochlear crest; radial bicipital tuberosity not present or barely insinuated; astragalus with wide and low trochlea, short neck, and variable nuchal crest; and a calcaneus with a rectangular fibular facet, half the length of the ectal facet, and an unusually thick sustentaculum. Isotemnus shares some of these features, but in other aspects, it is more similar to smaller typotherian taxa; the astragalar neck is better developed, and a crest is present on the calcaneal body that is absent in Periphragnis. These differences could be due to the smaller size of Isotemnus and its earlier divergence from other toxodontians and could help elucidate the most basal morphology of Notoungulata.