Fluids extracted from aqueous fluid inclusions in epigenetic gangue and ore minerals record the migration of huge volumes of highly saline fluids throughout the stratigraphic section of the Ozark region. The extracted fluids share many similarities regionally, but there are significant temporal differences which define two geochemically distinct end-member ore-forming fluids that we refer to as the Viburnum Trend main stage or Viburnum Trend type and the Tri-State type.Viburnum Trend-type fluids are enriched in potassium and are associated only with deposits close to the basal Lamotte Sandstone. The main-stage octahedral galena ore of the Viburnum Trend and much of the Old Lead Belt ore is thought to be derived from this type of ore fluid. Galena deposited by Viburnum Trend-type fluids contains less radiogenic lead than galena deposited by Tri-State-type fluids. Sulfides deposited by Viburnum Trend-type fluids also contain isotopically heavier sulfur and significant amounts of copper, cobalt, nickel, and silver.Tri-State-type fluids have a low potassium content when compared with Viburnum Trend-type fluids and are characteristic of deposits where ore-forming fluids migrated through large volumes of carbonate rock. These fluids are thought to have formed the ore deposits of the Tri-State, Northern Arkansas, and Central Missouri districts, the cubic galena-stage ore of the Viburnum Trend, and the many trace occurrences of sphalerite throughout the Ozark region. Galena deposited by Tri-State-type fluids has more radiogenic lead and the sulfides have isotopically lighter sulfur than sulfides deposited by Viburnum Trend-type fluids. A systematic south to north increase of potassium in the Tri-State-type fluids suggests that they migrated from a southerly source such as the Arkoma basin.Possible explanations for the origins of these two end-member fluids include: (1) a single parent brine evolved into two distinct fluids due to reactions with geochemically distinct aquifers during migration, (2) the two distinct fluids reflect normal fluid evolution within a single source basin of a bittern and of later halite dissolution, and (3) the Viburnum Trend and Tri-State-type brines migrated to southeast Missouri from two different source basins. Our data does not preclude any of these possibilities; however, the geochemical similarity of the Viburnum Trend end-member fluid to a bittern may be accounted for by water-rock modifications of the brine during migration. Other evidence strongly supports a southerly source for the ore-forming brines thus limiting possible sources for the Viburnum Trend-type fluid to the Arkoma and/or Black Warrior basins of the Ouachita foreland trough. Viburnum Trend-type fluid flow was probably funneled northward through basal sandstones within the Reelfoot rift and water-rock modifications occurring there may have resulted in its unique geochemistry.