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Located in the Cordillera de la Costa of northern Chile, the mines of the Mantoverde district exploit super-gene oxide ore developed over several Lower Cretaceous, hematite-rich, iron oxide-Cu-Au (IOCG) deposits with an average protore grade of 0.52 percent Cu and 0.11 g/t Au (e.g., Mantoverde proper, Manto Ruso). The geologic setting and genesis of this productive IOCG district are clarified herein through regional petrologic and lithogeochemical study and light stable isotope analysis of paragenetically constrained samples from Mantoverde and its satellite deposits. Together with chalcopyrite-bearing, but subeconomic, bodies of metasomatic magnetite (e.g., Montecristo and Franco) and Cu-barren magnetite-fluorapatite-pyrite bodies (e.g., Ferrifera), the deposits of the Mantoverde district were emplaced along the main and, more commonly, subsidiary segments of the plate boundary-parallel Atacama fault system. They are hosted by Middle to Upper Jurassic andesites of the La Negra Formation and diorites and monzodiorites assigned to the Lower Cretaceous Sierra Dieciocho plutonic complex. Prior to mineralization, the Jurassic and Neocomian igneous rocks of this Andean transect were subjected to moderate albitization (spilitization) and hydrolytic alteration and, subsequently, to regional, nondeformational metamorphism, which locally attained the lower greenschist facies. Both processes, however, were focused along the western margin of a Neocomian marginal basin, 25 to 30 km east of the Atacam fault system, and there is no evidence of widespread albitization in the vicinity of the major IOCG centers. An extensively revised paragenetic model for Mantoverde and its satellite deposits incorporates four stages. Stage I was dominated by widespread potassium and iron metasomatism which converted granitoid and volcanic rocks to orthoclase and magnetite, respectively. Stage II comprises chloritic and sericitic alteration and veining. The deposition, early in stage II, of marialitic scapolite, subsequently largely replaced by chlorite, was probably contemporaneous with regional scapolitization in the area between the Atacama fault system and the marginal basin. Chalcopyrite deposition was restricted to the ensuing stage III, hosted by calcite veins and, particularly, specular hematite-dominated hydrothermal breccias and stockworks. Stage IV barren calcite-quartz vein swarms record the terminal hydrothermal activity. Stable isotope fractionation relationships and published fluid inclusion microthermometry define a retrograde thermal evolution, from above ~460°C in stage I, through ~350°C in stage II, to ~210° to 280°C in ore stage III, and ~110° to 240°C in stage IV. The δ34S values of chalcopyrite and pyrite from Mantoverde and its associated orebodies and prospects range overall from −6.8 to +11.2 per mil, overlapping extensively. However, the narrow range, −0.6 to +2 per mil, of δ34S values of pyrite associated with stage I magnetite contrasts with the much wider range, −1.2 to +9.1 per mil, of that deposited in stage II. The compositional variability increases from +1.4 to −11.2 per mil in the mineralized assemblages of stage III, chalcopyrite generally having higher values than pyrite. The iron oxides in the district have δ18O values that vary overall from −1.9 to +4.1 per mil, the highest values, +1.4 to +4.1 per mil, occurring in stage I metasomatic magnetite, whereas stage III hematite has lower values of −2.0 to +1.7 per mil. Estimated equilibrium δ34Sfluid values increased dramatically with time, from +0.4 to +4 per mil in stage I, through +9.1 to +14.9 per mil during stage II, to +26.4 to +36.2 per mil for the most richly mineralized hematitic breccias. Stage III hematite equilibrated with a fluid with δ18O values of +3.0 to +8.0 per mil, significantly lower than those of fluids from which stage I magnetite crystallized (i.e., +7.3 to +9.9‰). The fluids responsible for barren stage I magnetite-pyrite assemblages, with δ34S and δ18O values close to 0 and +8 per mil, respectively, may have been products of the second boiling of granitoid magmas, possibly of the Sierra Dieciocho complex. Markedly higher δ34S and lower δ18O values in stages II and, particularly, stage III, in which all significant chalcopyrite and gold were deposited, are interpreted as evidence for the incursion of modified seawater, possibly via evaporitic sediments. Such externally derived fluids, probably mobilized by marginal basin inversion and recorded by the district-wide scapolitization (Na-Cl metasomatism), may have been a prerequisite for hypogene Cu(-Au) mineralization in the Mantoverde district.