The systematics of Hypoptopoma Günther (1868a) is revised based on comprehensive evaluation of specimen collections and a phylogenetic analysis of the species. The genus Hypoptopoma comprises a distinctive assemblage of loricariid catfishes distributed in the lowland drainages of tropical, subtropical, and temperate latitudes of South America to the east of the Andes. Hypoptopoma is uniquely diagnosed among genera of the Loricariidae on the basis of the presence of a laterally expanded nuchal plate. Members of the genus can be further distinguished from all other loricariids, except the hypoptopomatin genus Oxyropsis, by the depressed head with eyes placed ventrolateral and visible from below. Hypoptopomais further distinguished from all other Hypoptopomatini, including Oxyropsis, by the caudal peduncle posterior to the base of the anal fin ovoid in cross section and deeper in the dorsoventral axis. All species of Hypoptopoma, except H. spectabile, can be further distinguished among loricariids by the presence in adult stages of a column of variably enlarged and flattened odontodes positioned along the posterior margin of the trunk plates. Individuals of several Hypoptopoma species attain the largest body size for the subfamily Hypoptopomatinae, with standard length reaching 105 mm. Species of Hypoptopoma typically occur in streams of slow to moderate current and muddy to sandy bottom with marginal emergent vegetation. Based on verified specimen records, the species is distributed in the Río Amazonas basin, including the Ucayali, Madeira, and Tapajos rivers, as well as in the rivers east to the Ilha Marajo drainage (Para, Brazil), in the Tocantins and smaller coastal river drainages in northeastern Brazil (Mearim), the upper Río Orinoco basin, the Essequibo and Nickerie river basins of the Guiana Shield, and in the ríos Paraguay and lower Paraná. There are no records of Hypoptopoma in the Río Uruguay, the Atlantic coastal drainages of Uruguay and Brazil south of Rio Mearim (Maranão), the upper Paraná, and Rio São Francisco systems. Fifteen species are recognized in Hypoptopoma, seven of which are newly described herein. Phylogenetic analysis of Hypoptopoma species, based on analysis of 26 characters drawn from aspects of external morphology and internal osteology, recovered a well-supported but incompletely resolved nested set of clade relationships that suggests a widespread ancestral distribution for the group in central Amazonia, plus at least four instances of divergence of a species having a peripheral distribution from an Amazonian sister group. Relationships at the basal node were unresolved. There was insufficient evidence to resolve the relationships among H. baileyi, n. sp., of the Madeira river basin, an unresolved clade comprised of H. guianense Boesemann, 1974, of the Essequibo and Nickerie basins in Guyana and Surinam; H. psilogaster Fowler, 1915, of the upper Amazon basin in Brazil and Peru; and H. thoracatum Günther, 1868a, of the upper and middle Amazon basin; and a well-supported clade that includes all other Hypoptopoma species. The latter clade was supported by four synapomorphies and includes H. brevirostratum, n. sp., of the upper Amazon basin in Brazil and Peru, H. muzuspi, n. sp., of the Tocantins basin, and a more restricted clade supported by six character-state changes comprising the remainder of the subfamily. Two species, H. spectabile (Eigenmann, 1914) of the upland Amazon and upper Orinoco river basins of Venezuela, Colombia, Ecuador, and Peru and H. sternoptychum (Schaefer, 1996a) of the lowland reaches of the Amazon river, formerly placed in the genus Nannoptopoma Schaefer, 1996, represent a clade most closely related to a nested subset of Hypoptopoma species. These former Nannoptopoma species are reassigned to Hypoptopoma, thus rendering the former generic name a subjective junior synonym of Hypoptopoma. Hypoptopoma bianale, n. sp., of the upper Amazon River basin in Brazil and Peru represents the sister group to a largely unresolved clade comprised of H. inexspectatum (Holmberg, 1893a) of the Paraguay-Paraná basin, H. steindachneri Boulenger, 1895, of the upper Amazon basin in Brazil and Peru, H. gulare Cope, 1878, of the upper Amazon basin, H. machadoi, n. sp., of the Orinoco basin, and a clade comprised of H. elongatum, n. sp., of the lower Tapajos and lower Trombetas rivers plus H. incognitum, n. sp., of the middle Amazon basin, Tocantins, and Mearim rivers. A key to the species of Hypoptopoma is provided.