Specimens of Oryzomys referable to the megacephalus complex (Musser et al., 1998) collected in the Parque Nacional Noël Kempff Mercado (PNNKM), eastern Bolivia, are discriminated from three other currently recognized species of that group (O. megacephalus, O. perenensis, O. laticeps) by analysis of cranial morphometrics and molecular sequence of the cytochrome b gene. The Bolivian sample has the closest genetic relationship to O. perenensis (Kimura 2-parameter genetic distance × 100: 14.8) and O. laticeps (distance 12.0), but the genetic distance is large. The Bolivian sample is clearly separated from the others by both principal component and discriminant function analyses of cranial and body variables. We here describe it as a new species. Morphologically, it is intermediate in size, along with O. perenensis, between the smaller O. megacephalus and the larger-bodied O. laticeps. In pelage color and occlusal pattern it closely resembles O. megacephalus. The geographic range appears to be a relatively small area of the western basin of the Río Itenez that drains easternmost Santa Cruz and Beni Departments. Genetically verified populations of the four species are thus far allopatric, with the known range of the new species wedged between the geographic ranges of O. perenensis to the west and O. megacephalus to the east.