A regional isotopic study of Pb and S in hydrothermal galenas and U-Pb and S in potential source rocks was carried out for part of Moravia, Czech Republic. Two major generations of veins, (syn-) Variscan and post-Variscan, are defined based on the Pb-isotope system together with structural constraints (local structures and regional trends). The Pb-isotopic compositions of galena plot in two distinct populations with outliers in 206 Pb/ 204 Pb-207 Pb/ 204 Pb space. Galena from veins hosted in greywackes provides a cluster with the lowest Pb-Pb ratios: 206 Pb/ 204 Pb = 18.15-18.27, 207 Pb/ 204 Pb = 15.59-15.61, 208 Pb/ 204 Pb = 38.11-38.23. Those hosted in both limestones and greywackes provide the second cluster: 206 Pb/ 204 Pb = 18.37-18.44, 207 Pb/ 204 Pb = 15.60-15.63, 208 Pb/ 204 Pb = 38.14-38.32. These clusters suggest model Pb ages as Early Carboniferous and Triassic-Jurassic, the latter associated with MVT-like deposits. Two samples from veins hosted in Proterozoic rocks lie outside the two clusters: in metagranitoid ( 206 Pb/ 204 Pb = 18.55, 207 Pb/ 204 Pb = 15.64, 208 Pb/ 204 Pb = 38.29) and in orthogneiss ( 206 Pb/ 204 Pb = 18.79, 207 Pb/ 204 Pb = 15.73, 208 Pb/ 204 Pb = 38.54).The results from these two samples suggest an interaction of mineralizing fluids with the radiogenic Pb-rich source (basement?). The values of d 34 S suggest the Paleozoic host rocks (mostly -6.7 to +5.2& CDT) as the source of S for hydrothermal sulfides (mostly -4.8 to +2.5& CDT). U-Pb data and Pb isotope evolutionary curves indicate that Late Devonian and Early Carboniferous sediments, especially siliciclastics, are the general dominant contributor of Pb for galena mineralization developed in sedimentary rocks. Plumbotectonic mixing occurred, it is deduced, only between the lower and the upper crust (the latter involving Proterozoic basement containing heterogeneous radiogenic Pb), without any significant input from the mantle. It is concluded that in the Moravo-Silesian and Rhenohercynian zones (including proximal districts in Poland) lead and sulfur have been mobilized from the adjacent rocks during multiple hydrothermal events in processes that are remarkably comparable in timing, geochemistry of fluids and nature of sources.