Abstract: With proven reserves of more than 5Mt and predicted resources of 18Mt, the Huayuan Pb-Zn ore deposit located on the southeastern margin of the Yangtze Craton is one of the most famous giant Pb-Zn deposits in the Hu'nan-Guizhou metallogenic belt.This paper reports S, Pb, Sr isotopic compositions of ore minerals with the purpose of understanding the sources of ore metals and the genesis of the deposit.The ore sulfides have a narrow range of δ³⁴S values (from 24.5‰ to 34.7‰ with an average value of 30.2‰), suggesting that the sulfur was derived from the carbonate sulfate by thermochemical reduction during which the organic mat-ters played an important role.The ²⁰⁶Pb/²⁰⁴Pb, ²⁰⁷Pb/²⁰⁴Pb, ²⁰⁸Pb/²⁰⁴Pb ratios of sulfides range from 18.139 to 18.678, from 15.691 to 15.832, and from 38.300 to 39.255, respectively.The relatively homogeneous Pb isotopic ratios are similar to the data of the upper crust, indicating that the underlying strata with high Pb-Zn content probably provided a lot of metal materials for ore mineralization.The ⁸⁷Sr/⁸⁶Sr values (from 0.70915 to 0.70996) of sphalerite are higher than the ⁸⁷Sr/⁸⁶Sr ratios (from 0.70885 to 0.70909) of the host rock of the Lower Cambrian Qingxudong Formation, implying that the ore-forming fluids probably migrated through the basement rocks and induced the increase of Sr isotopes through water-rock reactions.Precipitation of ore minerals was attributed to the mix-ture of two types of fluids in appropriate structures, i.e., fluid enriched with metal materials and fluid with organic matter and sulfate.