The Mantoverde area of the III Región of northern Chile hosts numerous copper(–gold) deposits and prospects assigned to the iron oxide–copper–gold (IOCG) clan. These range from sulphide-poor magnetite–apatite–actinolite bodies (e.g. Carmen) to chalcopyrite-rich, hematite-cemented breccias and veins (e.g. Mantoverde, Cerro Negro and Palmira). The most important Cu-rich deposits are associated with the main or, more commonly, subsidiary structures of the plate-boundary-parallel Atacama Fault System, and are hosted by Middle to Upper Jurassic andesites and Lower Cretaceous dioritic to quartz dioritic plutons. The rocks in the wider Mantoverde area exhibit a complex evolution involving early sub-seafloor albitization (stage R1), subsequent, very low-grade diastathermal metamorphism (R2), and more local stage I K and Fe metasomatism and stage II hydrolysis, all preceding the emplacement of sulphide-bearing hematitic breccias and veins (i.e. ore-stage III). We develop a lithogeochemical exploration protocol specifically for Cu-rich IOCG-type deposits hosted by calc-alkaline volcano-plutonic terrains, based on the integration of whole-rock molar element ratios and oxygen isotope chemistry. Zirconium, the most conserved (least mobile) element in the volcanic and plutonic rocks of the area, was used as a common denominator for molar element ratios. The molar ratios Na/Zr, K/Zr and Al/Zr indicate that the host rocks proximal to the major deposits were affected by sodium depletion and potassium enrichment. The molar ratio (14Ca+19Na−14CO 2 )/(6Si+Al+2Fe+2Mg), recalculated to a percentage scale, constitutes a modified alteration index which can be used to quantify the degree of hydrothermal alteration in the host rocks. However, although this index differentiates barren from potentially prospective sectors (i.e. strongly altered host rocks), it does not identify the hydrolytically altered rocks that are closely associated with economic copper mineralization. The δ 18 O values of igneous rocks in the Mantoverde area vary widely from +4.2 to +14.1‰. Integrating the modified lithogeochemical alteration index with whole-rock δ 18 O values differentiates the least altered volcanic and plutonic rocks (i.e. alteration index <30%), with δ 18 O values close to +7‰, from moderately altered volcanic rocks (alteration index of 30 to 65%) having higher δ 18 O values of +10 to +13.2‰ due to enrichment in 18 O during regional metasomatism hydrothermal alteration sub-seafloor related to albitization and metamorphism. A third group comprises strongly K-feldspathized, Fe-metasomatized and chloritized rocks localized in Cu-mineralized centres which have alteration indexes exceeding 65% and δ 18 O values of +4.2 to +14.1‰. The δ 18 O values of paragenetically related minerals indicate that barren, K- and Fe-metasomatized host rocks equilibrated with magmatically derived fluids at temperatures exceeding 420°C. Although no recognizable alteration haloes are associated with the ensuing lower-temperature Cu-(Au) ore stage (III), the genetically related hydrolytic alteration (II) which preceded it generated distinctive alteration indices and Na/Al and K/Al ratios, as well as δ 18 O values averaging +10‰, with chlorite O and H isotope compositions indicating equilibration with non-magmatic fluids. We propose, in combination, that these parameters can be used to vector onto Cu-rich IOCG-type mineralization in Andean, calc-alkaline terrains.