The Huayuan Pb-Zn ore district in China, located in western Hunan Province, is a giant carbonate-hosted Pb-Zn ore district. The source of ore-forming brines in this ore district remains poorly constrained. Whether the highly saline brines are derived from evaporated seawater or dissolved evaporates continues to be intensely debated. Carbonate minerals associated with Pb-Zn mineralization have δ13CV-PDB and δ18OV-SMOW values ranging from ?5.55‰ to +1.35‰ (mean value of ?0.69‰; n = 14) and +16.28‰ to +25.05‰ (mean value of +20.22‰; n = 14), respectively. This indicates that carbonate minerals are dominantly formed from dissolved ore-hosted carbonate rocks. The δ34S values of sulfides range from +20.2‰ to +36.8‰, with an average value of +30.0‰ (n = 27). These results suggest that sulfur is predominantly derived from the thermochemical sulfate reduction of marine sulfate. The crush-leach analyzed solute data of fluid inclusions in sphalerite show the ore-forming fluids have Cl/Br molar ratios range from 118 to 384, and Na/Br molar ratios from 39 to 160 (n = 8). These Cl/Br ratios of hydrothermal fluid are much lower than those of seawater (657 to 564), but are consistent with bittern brines through early halite precipitation. We propose that ore-forming fluids are mainly derived from evaporitic basin brines, which leached base metals from the basement and/or country rocks. The brine then migrated to the basin margins through clastic rocks of basement and then precipitated sul?des by thermochemical sulfate reduction.