The extensive Changba-Lijiagou Pb-Zn deposit is located in the north of the Xihe–Chengxian ore cluster in West Qinling. The ore bodies are mainly hosted in the marble, dolomitic marble and biotite-calcite-quartz schist of the Middle Devonian Anjiacha Formation, and are structurally controlled by the fault and anticline. The ore-forming process can be divided into three main stages, based on field geological features and mineral assemblages. The mineral assemblages of hydrothermal stage Ⅰ are pale-yellow coarse grain, low Fe sphalerite, pyrite with pits, barite and biotite. The mineral assemblages of hydrothermal stage Ⅱ are black-brown cryptocrystalline, high Fe shalerite, pyrite without pits, marcasite or arsenopyrite replace the pyrite with pits, K-feldspar. The features of hydrothermal stage Ⅲ are calcite-quartz-sulfide vein cutting the laminated, banded ore body. Forty-two sulfur isotope analyses, twenty-five lead isotope analyses and nineteen carbon and oxygen isotope analyses were determined on sphalerite, pyrite, galena and calcite. The δ34S values of stage Ⅰ (20.3 to 29.0‰) are consistent with the δ34S of sulfate (barite) in the stratum. Combined with geological feature, inclusion characteristics and EPMA data, we propose that TSR has played a key role in the formation of the sulfides in stage Ⅰ. The δ34S values of stage Ⅱ sphalerite and pyrite (15.1 to 23.0‰) are between sulfides in the host rock, magmatic sulfur and the sulfate (barite) in the stratum. This result suggests that multiple S reservoirs were the sources for S2? in stage Ⅱ. The δ34S values of stage Ⅲ (13.1 to 22‰) combined with the structure of the geological and mineral features suggest a magmatic hydrothermal origin of the mineralization. The lead isotope compositions of the sulfides have 206Pb/204Pb ranging from 17.9480 to 17.9782, 207Pb/204Pb ranging from 15.611 to 15.622, and 208Pb/204Pb ranging from 38.1368 to 38.1691 in the three ore-forming stages. The narrow and symmetric distributions of the lead isotope values reflect homogenization of granite and mantle sources before the Pb-Zn mineralization. The δ13CPDB and δ18OSMOW values of stage Ⅰ range from ?0.1 to 2.4‰ and from 18.8 to 21.7‰. The values and inclusion data indicate that the source of fluids in stage Ⅰ was the dissolution of marine carbonate. The δ13CPDB and δ18OSMOW values of stage Ⅱ range from ?4 to 1‰ and from 12.3 to 20.3‰, suggesting multiple C-O reservoirs in the Changba deposit and the addition of mantle-source fluid to the system. The values in stage Ⅲ are ?3.1‰ and 19.7‰, respectively. We infer that the process of mineralization involved evaporitic salt and sedimentary organic-bearing units interacting through thermochemical sulfate reduction through the isotopic, mineralogy and inclusion evidences. Subsequently, the geology feature, mineral assemblages, EPMA data and isotopic values support the conclusion that the ore-forming hydrothermal fluids were mixed with magmatic hydrothermal fluids and forming the massive dark sphalerite, then yielding the calcite-quartz-sulfide vein ore type at the last stage. The genesis of this ore deposit was epigenetic rather than the previously-proposed sedimentary-exhalative (SEDEX) type.