The Mississippi Valley-type (MVT) Zn–Pb–Ag deposit in the Wiesloch area, Southwest Germany, is controlled by graben-related faults of the Upper Rhinegraben. Mineralization occurs as vein fillings and irregular replacement ore bodies consisting of sphalerite, banded sphalerite, galena, pyrite, sulfosalts (jordanite and geocronite), barite, and calcite in the Middle Triassic carbonate host rock. Combining paragenetic information, fluid inclusion investigations, stable isotope and mineral chemistry with thermodynamic modeling, we have derived a model for the formation of the Wiesloch deposit. This model involves fluid mixing between ascending hot brines (originating in the crystalline basement) with sedimentary formation waters. The ascending brines originally had a near-neutral pH (around 6) and intermediate oxidation state, reflecting equilibrium with granites and gneisses in the basement. During fluid ascent and cooling, the pH of the brine shifted towards more acidic (around 4) and the oxidation state increased to conditions above the hematite-magnetite buffer. These chemical characteristics contrast strongly with those of the pore and fracture fluid residing in the limestone aquifer, which had a pH between 8 and 9 in equilibrium with calcite and was rather reduced due to the presence of organic matter in the limestone. Mixing between these two fluids resulted in a strong decrease in the solubility of silver-bearing sphalerite and galena, and calcite. Besides Wiesloch, several Pb–Zn deposits are known along the Upper Rhinegraben, including hydrothermal vein-type deposits like Badenweiler and the Michael mine near Lahr. They all share the same fluid origin and formation process and only differ in details of their host rock and fluid cooling paths. The mechanism of fluid mixing also seems to be responsible for the formation of other MVT deposits in Europe (e.g., Réocin, Northern Spain; Trèves, Southern France; and Cracow-Silesia, Poland), which show notable similarities in terms of their age, mineralogy. and mineral chemistry to the MVT deposit near Wiesloch.