In the Kalahari Copperbelt, the mechanism of regional scale Cu-Ag mineralization has remained intensely debated between early diagenesis and a single pass during a regional deformation event. At the Zone 5 Cu-Ag deposit in northwestern Botswana, the orebody is hosted preferentially by chemically reduced metasedimentary rocks that overly oxidized, hematite-bearing arkosic sandstone. An early diagenetic mineralizing event has been identified which is characterized by fine-grained stratiform pyrite, including recrystallized framboidal pyrite, intergrown with diagenetic mineral assemblages in the host-rock. Diagenetic pyrite is in textural equilibrium with chalcopyrite, sphalerite, galena, and (Fe-Co-Ni) sulfarsenide. These minerals were subsequently overprinted by a more intense, multi-stage, structurally-controlled hydrothermal Cu-Ag mineralization event related to the Damaran orogeny ($600-480 Ma). The hydrothermal Cu-Ag mineralization was deposited from hot ($236-265 C), high salinity (19-24.6 wt% NaCl equiv.) hydrothermal ore fluids. Petrographic results reveal an apparent overlap in trace metal associations (Cu, Fe, As, Zn, Pb, Ni, Co) between the two mineralizing events, which can be explained by remobilization of precursor sulfides. The major Ag-carriers in the ore are chalcocite, covellite, and bornite. The δ 34 S values of diagenetic pyrite range from À35.8 to +11.4‰, whereas those of hydrothermal epigenetic sulfides, including pyrite, range from À28.0 to +3.0‰. We propose that the hydrothermal sulfides had acquired some bacterially-reduced sulfur from earlier-formed minerals. The δ 18 O and δ 13 C values of quartz and calcite associated with the hydrothermal mineralization are typical of Neoproterozoic sediment-hosted Cu-Ag deposits. However, the δ 18 O isotopic values of the calcite gangue are anomalously depleted, which is likely due to recrystallization under metamorphic conditions. Our studies at Zone 5 indicate that the Zone 5 Cu-Ag deposit is the result of a multi-stage mineralization history that includes both diagenetic and epigenetic events (punctuated by >400 m.y.) facilitated by a strong litho-structural control.