The Prominent Hill iron oxide-copper-gold (IOCG) deposit, located in the Gawler craton of South Australia, contains ca. 278 million metric tons (Mt) of ore at 0.98% Cu, 0.75 g/t Au, and 2.5 g/t Ag. In contrast to the predominantly granite-hosted Olympic Dam IOCG deposit, Prominent Hill is mainly within unmetamorphosed sedimentary rocks comprising coarse clastic to laminated argillaceous lithologies with some volcaniclastic components and variable carbonate, including local massive dolomite. Essentially unmetamorphosed sedimentary rocks and structurally underlying mafic to intermediate-composition lavas, inferred to be members of the lower Gawler Range Volcanics, host the economically mineralized hematite breccias. The volcanic-sedimentary package was downfaulted and tilted along a major east-west fault, north of which similar but regionally low-grade metamorphosed rocks were affected by subeconomic skarn mineralization, and (on a more regional scale of the Mount Woods domain) intruded by granitic and gabbroic bodies. Hydrothermal alteration and mineralization at Prominent Hill involved pervasive and texturally destructive replacement of formerly calcareous, dolomitic, and siliciclastic breccia components. Hydrothermal alteration minerals comprise hematite, magnetite, siderite, ankerite, quartz, sericite, chlorite, kaolinite, fluorapatite, fluorite, barite, REE-U minerals (including monazite), uraninite, and coffinite, together with Cu sulfides including chalcopyrite, bornite, and chalcocite in the highest grade ore. Brecciation and replacement caused mechanical mixing as well as chemical alteration of primary lithologies, such that sedimentary contacts became obscured. Mass-balance calculations identify Al, Ti, Si, and Zr as least mobile components during hematite-chlorite-sericite to weak hematite-quartz alteration. Because Zr was not regularly assayed in drill cores, we use concentration ratios of Ti, Al, and Si from the deposit-scale assay database to delineate the distribution of lithochemical units prior to hydrothermal alteration and Cu mineralization. The resulting lithochemical model, based on one horizontal and five vertical cross sections, is used as a basis for mapping alteration patterns calculated from molar (Fe + Si)/(Fe + Si + Al), K/Na, and K/Al ratios. These chemical patterns, in conjunction with mineral stoichiometry, indicate that the spatial distribution of hematite, chlorite, variably phengitic sericite (and/or illite) ± kaolinite ± quartz-bearing alteration is superimposed on the pattern of interpreted lithologic contacts. The alteration patterns confirm visual logging results, showing that hematite enrichment correlates only partially with the distribution of Cu grades of >0.25 wt %. A subvertical body of complete replacement by hematite and quartz with consistent but subeconomic gold enrichment forms a Cu-barren core in the central and eastern parts of the deposit. Zones of increasing K/Al and K/Na ratios extend upward and westward from this Cu-barren core, transgressively overprinting lithologic contacts. The degree of hematite-quartz replacement can be measured by a hematite-quartz alteration index, here termed the HMSI value [(Fe + Si)/(Fe +Si + Al)], which inversely correlates with the normal probability for Cu grade. Areas of highest Cu grade (>1 wt %) spatially correlate with irregular zones having intermediate molar alteration indices: 0.34 < K/Al < 0.40, 20 < K/Na < 36, and HMSI < 0.98. Hematite breccias and Cu ore deposition developed after tilting of the host sequence into its present steep orientation, as indicated by geopetal structures within the breccia matrix. Thus, the economic mineralization occurred late in the deformational history of the region and after extrusion of the lower Gawler Range Volcanics. The formation of the Prominent Hill orebodies occurred during or after upthrusting of deeper seated rocks containing subeconomic Cu in skarns north of the fault. Faulting as well as ore formation may be related to orogenic processes in the central and northern part of the Mount Woods domain. Iron oxide introduction was decoupled from, and at least partly preceded, hydrothermal deposition of high-grade Cu. Geochemical and petrographic data indicate that economic Cu mineralization occurred together with mildly acidic hematite-chlorite-sericite ± siderite alteration of originally carbonate-, illite-, and feldspar-bearing sedimentary rocks. The presence of copper enrichment with an intermediate degree of cation leaching from the host rocks indicates that pH neutralization of initially highly acidic metal-transporting fluids was an essential factor causing Cu sulfide deposition. Distinct ranges in Na-K-Al ratios and low HMSI values offer potential as exploration indicators pointing toward higher ore grades. These results from Prominent Hill are consistent with recently published mineralogical studies at the giant Olympic Dam deposit, indicating similar ore depositional controls despite lithologically different host rocks.