Unraveling the time-space evolution of Mississippi Valley-type (MVT) hydrothermal systems is critically important for understanding ore genesis and exploration. We studied a complete mineral system from conduit-filling to tail-end facies in the world-class Sichuan–Yunnan–Guizhou triangle, South China, via field geology, mineralogy, fluid inclusions, and in situ sulfide S-Pb isotopes to propose an integrated model for the evolution of MVT hydrothermal systems. Geological mapping shows that the mineralization transitions from breccia pipe to stratabound style: high-grade ores occur mainly as open-space infill associated with F12 fault (fluid conduit), while low-grade evaporite-related replacement ores developed distal from the fault. The δ34S value in hydrothermal sulfides shows a wide range (+3.6‰ to +27.9‰), with significant intragrain variation (up to +12.8‰), which suggests a mixture of 34S-rich sulfur produced by thermochemical sulfate reduction of evaporite within the ore host and 32S-rich sedimentary/diagenetic pyrite. In situ sulfide Pb ratios decrease away from the F12 fault, which indicates that metals were sourced from different degrees of mixing between the Proterozoic metamorphic basement and wall rocks. Fluid-inclusion microthermometric data identify two distinct fluids: a hotter (>155 °C), more saline (>18 wt% NaCl equivalent), and metal-rich fluid with a cooler (<90 °C), low-salinity (<4 wt% NaCl equivalent), and reduced sulfur-rich fluid. The mixing of two fluids was responsible for precipitating the high-grade ores near the F12 fault, and the acid-producing (H+) process created new space for stratabound ore distal to the fault. This study highlights that fluid mixing is critical for efficient sulfide accumulation, and the metal zoning pattern provides guidelines for exploration.

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