The carbonate-hosted Pb–Zn deposits in the Sanjiang metallogenic belt on the Tibetan Plateau are typical of MVT Pb–Zn deposits that form in thrust-fold belts. The Jiamoshan Pb–Zn deposit is located in the Changdu area in the middle part of the Sanjiang belt, and it represents a new style of MVT deposit that was controlled by karst structures in a thrust–fold system. Such a karst-controlled MVT Pb–Zn deposit in thrust settings has not previously been described in detail, and we therefore mapped the geology of the deposit and undertook a detailed study of its genesis. The karst structures that host the Jiamoshan deposit were formed in Triassic limestones along secondary reverse faults, and the orebodies have irregular tubular shapes. The main sulfide minerals are galena, sphalerite, and pyrite that occur in massive and lamellar form. The ore-forming fluids belonged to a Mg2+–Na+–K+–SO42?–Cl?–F?–NO3?–H2O system at low temperatures (120–130°C) but with high salinities (19–22% NaCl eq.). We have recognized basinal brine as the source of the ore-forming fluids on the basis of their H–O isotopic compositions (?145‰ to ?93‰ for δDV-SMOW and ?2.22‰ to 13.00‰ for δ18Ofluid), the ratios of Cl/Br (14–1196) and Na/Br (16–586) in the hydrothermal fluids, and the C–O isotopic compositions of calcite (?5.0‰ to 3.7‰ for δ13CV-PDB and 15.1‰ to 22.3‰ for δ18OV-SMOW). These fluids may have been derived from evaporated seawater trapped in marine strata at depth or from Paleogene–Neogene basins on the surface. The δ34S values are low in the galena (?3.2‰ to 0.6‰) but high in the barite (27.1‰), indicating that the reduced sulfur came from gypsum in the regional Cenozoic basins and from sulfates in trapped paleo-seawater by bacterial sulfate reduction. The Pb isotopic compositions of the galena samples (18.3270–18.3482 for 206Pb/204Pb, 15.6345–15.6390 for 207Pb/204Pb, and 38.5503–38.5582 for 208Pb/204Pb) are similar to those of the regional Triassic volcanic-arc rocks that formed during the closure of the Paleo-Tethys, indicating these arc rocks were the source of the metals in the deposit. Taking into account our new observations and data, as well as regional Pb–Zn metallogenic processes, we present here a new model for MVT deposits controlled by karst structures in thrust–fold systems.