Two nominal species of Neotropical murid rodents (subfamily Sigmodontinae) that have long been referred to different genera are here placed in a new genus in recognition of their distinctness from other named supraspecific taxa. Aepeomys fuscatus Allen and Oryzomys intectus Thomas share a unique combination of external and craniodental character states that diagnose Handleyomys, new genus, with fuscatus as its type species. Morphological comparisons of Handleyomys with the type species of Aepeomys Thomas and Oryzomys Baird provide a basis for preliminary inferences about phylogenetic relationships. Five shared, derived character states support the hypothesis that Handleyomys is an oryzomyine, but no close relationship between the new genus and any particular oryzomyine clade is indicated by the data at hand. All known specimens of Handleyomys are from the western Andes (Cordillera Occidental) and the central Andes (Cordillera Central) of Colombia, where they have been collected at 20 localities ranging in elevation from 1500 to 2800 m above sea level. Analyses of morphological data suggest that two valid allopatric species are represented, of which H. fuscatus is endemic to the western Andes and H. intectus to the central Andes. Although no other mammalian clade is known to have the same geographic distribution, recent analyses of amphibian biogeography in Colombia suggest that Handleyomys is part of a nonvolant cloud-forest vertebrate fauna with allopatric sister taxa in the Cordillera Occidental and Cordillera Central. Much revisionary taxonomic research, however, is needed to assess the generality of this pattern of endemism among other cloud-forest mammals.