The Ozark region of the U.S. midcontinent is host to a number of Mississippi Valley-type districts, including the world-class Viburnum Trend, Old Lead Belt, and Tri-State districts and the smaller Southeast Missouri barite, Northern Arkansas, and Central Missouri districts. There is increasing evidence that the Ozark Mississippi Valley-type districts formed locally within a large, interconnected hydrothermal system that also produced broad fringing areas of trace mineralization, extensive subtle hydrothermal alteration, broad thermal anomalies, and regional deposition of hydrothermal dolomite cement. The fluid drive was provided by gravity flow accompanying uplift of foreland thrust belts during the Late Pennsylvanian to Early Permian Ouaehita orogeny.In this study, we use chemical speciation and reaction path calculations, based on quantitative chemical analyses of fluid inclusions, to constrain likely hydrothermal brine compositions and to determine which precipitation mechanisms are consistent with the hydrothermal mineral assemblages observed regionally and locally within each Mississippi Valley-type district in the Ozark region. Deposition of the regional hydrothermal dolomite cement with trace sulfides likely occurred in response to near-isothermal effervescence of CO ₂ from basinal brines as they migrated to shallower crustal levels and lower confining pressures. In contrast, our calculations indicate that no one depositional process can reproduce the mineral assemblages and proportions of minerals observed in each Ozark ore district; rather, individual districts require specific depositional mechanisms that reflect the local host-rock composition, structural setting, and hydrology.Both the Northern Arkansas and Tri-State districts are localized by normal faults that likely allowed brines to rise from deeper Cambrian-Ordovician dolostone aquifers into shallower carbonate sequences dominated by limestones. In the Northern Arkansas district, jasperoid preferentially replaced limestones in the mixed dolostone-limestone sedimentary packages. Modeling results indicate that the ore and alteration assemblages in the Tri-State and Northern Arkansas districts resulted from the flow of initially dolomite-saturated brines into cooler limestones. Adjacent to fluid conduits where water/rock ratios were the highest, the limestone was replaced by dolomite. As the fluids moved outward into cooler limestone, jasperoid and sulfide replaced limestone. Isothermal boiling of the ore fluids may have produced open-space filling of hydrothermal dolomite with minor sulfides in breccia and fault zones. Local mixing of the regional brine with locally derived sulfur undoubtedly played a role in the development of sulfide-rich ore runs.Sulfide ores of the Central Missouri district are largely open-space filling of sphalerite plus minor galena in dolostone karst features localized along a broad anticline. Hydrothermal solution collapse during ore deposition was a minor process, indicating dolomite was slightly undersaturated during ore deposition. No silicification and only minor hydrothermal dolomite is present in the ore deposits. The reaction path that best explains the features of the Central Missouri sulfide deposits is the near-isothermal mixing of two dolomite-saturated fluids with different H ₂ S and metal contents. Paleokarst features may have allowed the regional brine to rise stratigraphically and mix with locally derived, H ₂ S-rich fluids. The Viburnum Trend and Old Lead Belt ores are galena rich with lesser amounts of sphalerite; they replace the most permeable dolostone facies in the Bonneterre Dolomite. Hydrothermal dissolution of host dolostone was concurrent with sulfide deposition, but dolomite deposition occurred episodically between periods of sulfide deposition. The important ore controls in these districts are a variety of sedimentary and geologic features that allowed cross-stratigraphic fluid flow and provided opportunities for fluid mixing. The reaction path which best reproduces the broad features of the Viburnum Trend and Old Lead Belt ores is one in which a dolomite-saturated, lead-rich, zinc- and H ₂ S-poor brine mixes with a less saline, H ₂ S-rich fluid. The brine became enriched in K, Mg, and Pb and depleted in H ₂ S as it flowed through sandstone and redbed aquifers prior to entering the district. This mixing model is consistent with the abundant fluid inclusion and stable isotope evidence for fluid mixing in the districts. Small amounts of cooling associated with the mixing may have contributed to sulfide deposition.