Oryzomyini. Derived postcranial traits of Megalomys are consistent with its association within Sigmodontinae sensu stricto (lack of entepicondylar foramen, tuberculum of 1^st rib contacting both the 1^st thoracic and 7^th cervical vertebrae; as per M. desmarestii, BMNH 1850.11.30.6); other cranial characters more narrowly point to its membership within Oryzomyini (long palate with prominent posterolateral pits, absence of alisphenoid strut; as per M. luciae, BMNH 53.12.16.2, and M. desmarestii, BMNH 50.11.30.6 and 55.12.24.201), as diagnosed by Voss and Carleton (1993). A combination of features suggests that the close relatives of Megalomys may be sought among certain derived oryzomyines, such as Oryzomys sensu stricto, or Nectomys (e.g., thenar and hypothenar pads present but barely indicated; molars brachyodont and pentalophodont, with M1/m1 four-rooted; supraorbital and temporal ridging well developed and reflected dorsally; carotid circulation derived).

Named as a subgenus of the all-inclusive Hesperomys, later associated with Holochilus by Thomas (1884) or Oryzomys by Major (1901), and subsequently recognized as an oryzomyine genus endemic to the Lesser Antilles (Ellerman, 1941; Hall, 1981; Steadman and Ray, 1982; Tate, 1932c). Does not include the extinct Galápagos endemic curoi, described as a species of Megalomys by Niethammer (1964); see Steadman and Ray (1982) and account of Megaoryzomys. Morphology redescribed and taxonomy revised by Ray (1962) as a subgenus of Oryzomys, following the undeveloped opinions of Osgood (1947) and Hershkovitz (1948b). The four nominal species (audreyae Hopwood, 1926; curazensis Hooijer, 1959; desmarestii Fischer, 1829; luciae Forsyth Major, 1901) are extinct, possibly all due to anthropogenic causes, but M. desmarestii and M. luciae, listed below, persisted into the middle, perhaps late, 1800s (Ray, 1962; Woods, 1989). Known from Pleistocene-Holocene fossils, Pre-Columbian midden deposits, and a few modern specimens (Ray, 1962). See G. M. Allen (1942) for compilation of meagre historical accounts.