The Kengdenongshe giant Au-Ag-Pb-Zn polymetallic deposit is located in the East Kunlun Orogen (EKO). It contains about 42.2 t of Au, 608.6 t of Ag and 1.05 Mt of Pb and Zn with an average grade of Au 2.31 g/t, Ag 19.29 g/t and Pb + Zn 3.49 wt% (Pb: 1.23 wt%, Zn: 2.26 wt%). The NWW-trending ore bodies are predominantly hosted in Late Permian to Triassic rhyolitic tuff, which formed during Late Permian back-arc extension to Triassic arc-continental collision. The ore bodies are subdivided into Pb-Zn rich ore bodies on the top with high grades of Pb and Zn and low grades of Au and Ag, and Au-Ag rich ore bodies below with high grades of Au and Ag and low grades of Pb and Zn. The Pb-Zn rich ore bodies occur as vein, stockwork, and in breccia, and comprise quartz, pyrite, galena, sphalerite, and small amounts of chalcopyrite. The Au-Ag rich ore bodies consist of auriferous barite-sulfide-oxide veins and contain barite, pyrite (early strawberry and oolitic pyrite and later eu- to subhedral pyrite), galena, sphalerite, chalcopyrite, tetrahedrite and covellite. Gold is present as electrum, kustelite and native gold and silver is present as polybasite, pearceite, kongsbergite, and as minor native silver in microfractures in sulfides. The hydrothermal alteration minerals include, from bottom to top, quartz + barite + calcite around the Au-Ag rich orebodies, quartz + chlorite + epidote around the Pb-Zn rich orebodies, and quartz +K-feldspar within the tuff. Fluid inclusions from both the Pb-Zn rich and the Au-Ag rich orebodies consist of two phases (V?L-type) fluid inclusions of which the vapor phase has a size of 10?40 vol%. Fluid inclusions microthermometry reveal homogenization temperatures of fluid inclusions in Pb-Zn rich and Au-Ag rich ore bodies of 128?230 ?C and 110?320 ?C, with corresponding salinities of 0.7?9.9 and 0.2?18.3 wt% NaCl equivalent, respectively. H-O-S-Pb stable isotope and He-Ar noble gas isotope data indicate a mixed magmatic water-seawater source for both the Pb-Zn and Au-Ag rich ore bodies, and an additional meteoric water component for the Au-Ag rich ore bodies. The Pb-Zn and Au-Ag rich ore bodies share the same sulfur and lead sources, i.e. sulfur is derived from crustal magma and seawater/marine sulfate, and the lead originated from a mixed magmatic-ancient crustal sedimentary source. Collectively, the regional geology, mineralogy, alteration, and geochemistry indicate that the Kengdenongshe Au-Ag-Pb-Zn polymetallic deposit can be characterized as a VMS-type (volcanic-associated massive sulfide) deposit. Formation of the ore-hosting rhyolite tuff and mineralization are associated with Late Permian to Triassic marine volcanic exhalation. Middle to Late Triassic basin closure and arc-continent collision modified the deposit and resulted in the location inversion of the Pb-Zn and Au-Ag rich orebodies.