This species is found naturally in mountain forests of the Andes from central Peru through Bolivia; within this area it is rather widespread not only geographically but in elevational range. Cinchona calisaya is variable morphologically and apparently comprises some rather distinct subpopulations, however Andersson (1998) concluded that these are not completely differentiated but are linked by numerous intermediate and thus belong to one species (ochlospecies). The circumscription of C. calisaya and the status of some of its localized forms, particularly in Bolivia, may merit reconsideration now that many additional specimens from recent exploration are available that Andersson did not see.

Cinchona calisaya is one of the principal species that has been cultivated as a source of the febrifuge and antimalarial medicine quinine, which is derived from its bark. Cinchona calisaya has been confused for many years with C. officinalis; however Andersson (1998) clarified that C. officinalis is a separate species with a natural distribution that is restricted to southern Ecuador, so it does not grow together with C. calisaya, and which does not contain useful quantities of quinine in its bark and has not been widely cultivated.

Cinchona calisaya can be recognized by its rather stiff-textured leaves that often (though not always) have pit domatia in the axils of the veins on the lower surface, its medium-sized flowers with the corolla tube ca. 8-13 mm long, and its medium-sized fruits with rather stiff walls. This species is variable in several features including the amount of pubescence, the shape of its leaves, the size of its fruits, and the length of the calyx limb. In particular C. calisaya is similar to C. officinalis of southern Ecuador; Andersson (1998) noted that these species have separate geopgrahic ranges and distinguished them morphologically mainly by where the domatia in the leaves are found, mostly in the proximal (i.e., basal or bottom) part of the leaf in C. officinalis vs. produced mostly in the distal (i.e., apical or upper) part of the leaf or else not present in C. calisaya. Cinchona calisaya seems to be replaced to some extent to the north of its range by the similar species C. villosa; C. villosa is found in southern Ecuador and adjacent northern Peru and can be separated by its leaves with a papery texture and its usually smaller flowers, with the corolla tube 6-9 mm long.