The Wusihe Pb-Zn deposit, located at the southeastern margin of Yangtze Block, is one of the typical large-scale Pb-Zn deposits in the Sichuan-Yunnan-Guizhou (SYG) metallogenic province with an estimated Pb + Zn reverse > 3. 70Mt at an average grade of similar to 15. 7%. Sulfide orebodies were hosted in the dolostone of Sinian Dengying Formation, occurring as stratiform, stratoid and lenses with weak wall rock alteration. Sulfide ores are mainly massive, banded, breccias, veins and disseminated ores. The mineral assemblage of the Wusihe deposit is relatively simple, including sphalerite, galena, hydrothermal dolomite and calcite with minor pyrite, bitumen and quartz. The ore genesis of Wusihe remains controversial due to the lack of geological and geochemical studies, and related views about its mineralization include hydrothermal sedimentation, later hydrothermal superimposition on an exhalative sedimentation and MVT. In this study, in-situ S and Pb isotopes of sulfides (sphalerite, pyrite and galena) from Wusihe at different stages were investigated, aiming to: (1) constrain the sources of metals and the formation mechanism of reduced S; (2) to trace its ore-forming process; and further (3) to provide new evidence for understanding the ore genesis. In-situ S isotopic compositions in the Wusihe deposit show different S sources during ore-forming process. Sulfides at early ore-stage had significant depletion of S-34 and the delta S-34 values (ranging from +1. 3%o to +14. 2 parts per thousand), which may suggest that the H2S was derived from a paleo-petroleum system in host rock; while the delta S-34 values of sulfides at late ore-stage vary from + 11.0 parts per thousand to + 23. 3 parts per thousand, i. e., it is enriched in heavy S isotopes, indicating that it has undergone a marine sulfate thermochemical reduction of evaporate in ore-hosted strata. The LA-MC-ICPMS in-situ Pb isotopic ratios of sulfides (sphalerite and galena) show that the ore-forming metals of the Wusihe deposit are mainly derived from basement rocks with a small contribution from host rock via water-rock interaction. Geology and in-situ S and Pb isotope data, together with early published studies, suggest that the Wusihe deposit belongs to an MVT Pb-Zn deposit, and the metal-bearing fluid mixing with reduced S-enriched fluid is the key factor for metal sulfide precipitation.