Hypostomus khimaera can be diagnosed from all congeners, except those belonging to the H. cochliodon group, by having the following unique combination of characters: absence of notch between metapterygoid and hyomandibula (vs. presence of notch); and strongly angled dentaries, less than 80° (vs. shallow angle between dentaries, generally more than 80°). It differs from all members of the H. cochliodon group, except from H. basilisko and H. soniae, by the presence of a dark tan stripe along the flank (vs. absence). It can be distinguished from H. basilisko and H. soniae by having black spots on the body and fins or at least in one of these (vs. absence of spots). In addition, it can be further separated from H. basilisko by having moderately developed keels (vs. highly developed keels) and 28 vertebrae (vs. 27); and from H. cochliodon by having 12-27 teeth (vs. 7-9), externalized opercle, exposed region easily visible (vs. almost entire internalized opercle, exposed region not easily visible; and 28 vertebrae (vs. 29) (Ref. 97225).