The only species in the genus Pseudoryzomys, its closest living relatives are the large rats Holochilus and Lundomys, which are semiaquatic, spending much of their time in the water.

The three genera share several characters, including specializations towards a semiaquatic lifestyle, such as the presence of membranes between the digits (interdigital webbing), and a reduction in the complexity of the molar crowns, both of which are at incipient stages in Pseudoryzomys.

Together, they form a unique assemblage within the oryzomyine tribe, a very diverse group including over one hundred species, mainly in South America.

It was first described in 1888 by Danish zoologist Herluf Winge,[4] who reviewed the materials Peter Wilhem Lund had collected in the caves of Lagoa Santa, Minas Gerais, Brazil.

[7] In 1980, Argentinean zoologist Elio Massoia suggested that Winge's Hesperomys simplex and the living Pseudoryzomys wavrini are in fact the same species.

In a 1991 study, American zoologists Voss and Myers confirmed this suggestion after re-examining Winge's material, finding no appreciable differences among specimens of H. simplex and P. wavrini.

Voss and Myers also re-evaluated the relationships of Pseudoryzomys; they considered it closer to oryzomyines than to phyllotines, but declined to formally place it in Oryzomyini in the absence of explicit phylogenetic justification for such a placement.

Sigmodontinae itself is the largest subfamily of the family Cricetidae, other members of which include voles, lemmings, hamsters, and deermice, all mainly from Eurasia and North America.

[14] Several phylogenetic studies published during the 1990s and 2000s supported a close relationship between Pseudoryzomys and two other oryzomyines with reduced or absent mesoloph(id)s, Lundomys and Holochilus.

[15] In 2006, a broad morphological and molecular phylogenetic study of Oryzomyini provided further support for the relationship between Holochilus, Lundomys, and Pseudoryzomys.

Morphological data indicate that the genus Oryzomys is the closest relative of the group that includes Pseudoryzomys, but DNA sequence data from the nuclear IRBP gene did not support this relationship; convergent adaptations towards a semiaquatic lifestyle may explain the morphological support for a relation between Oryzomys and the other three genera.

[20] The female has four pairs of teats, including one on the chest and three on the belly, and the gall bladder is absent, both important characters of Oryzomyini.

The squamosal bone lacks a suspensory process contacting the tegmen tympani, the roof the tympanic cavity.

The two masseteric ridges, to which some of the chewing muscles are attached, are entirely separate, joining only at their front edges, which are located below the first molar.

[23] The hindmost valley between cusps on the lower first molar, the posteroflexid, is severely reduced, foreshadowing its loss in Lundomys and Holochilus.

[37] Unlike in most sigmodontines, including Holochilus and Lundomys, the fourth lumbar vertebra lacks the processes known as anapophyses.

However, in two specimens from the Brazilian states of Tocantins and São Paulo, one pair of autosomes contains both an acrocentric and a metacentric chromosome (with two equally long arms), yielding an FN of 55.

[42] Apparently, a whole heterochromatic arm was added to this chromosome; cases of similar variation are known from the rodents Peromyscus, Clyomys, and Thaptomys.

[43] Pseudoryzomys simplex is known from northeastern Argentina, probably south to about 30°S,[44] northward through western Paraguay to eastern Bolivia and from there eastward through Brazil in the states of Mato Grosso, Goiás, Tocantins, Minas Gerais, São Paulo, Bahia, and far in the northeast, Alagoas and Pernambuco.

Certain bats show a similar pattern of variation: they are smaller and paler in the Chaco region, which includes much of Paraguay.

[7] Two specimens from Paraguay, collected 600 kilometres (400 mi) apart, differed by 1.4% in the sequence of the cytochrome b gene,[46] but nothing is known about genetic variation in other parts of the range.

It is a widely distributed species without substantial threats to its continued existence, but degradation of its habitat may endanger some populations.