Strata-bound sulfide (Zn-Pb-Fe) and sulfate (Ba-Sr) mineralization occurs in Upper Mississippian (Arundian-Holkerian) limestone, primarily bryozoan-microbial mounds of the Big Cove Formation on the Port au Port Peninsula, western Newfoundland. Stages of host-rock petrogenesis and mineralization are compared by integrating structure, stratigraphy, petrography, and geochemistry (fluid inclusions, and C, O, S, Sr, and Pb isotopes). Strata-bound mineralization is linked to fault-controlled fluid flow through Ordovician (basement) carbonate and into porous Mississippian host rock, with subsequent fluid migration bounded by stratigraphic permeability barriers. Mineralization is preferentially juxtaposed to deposits of Mississippian gypsum, the most likely source of sulfate. The 87 S/ 86 Sr ratios in calcite associated with mineralization suggest that fluids were most likely generated from or had undergone isotopic exchange with lower Paleozoic strata, including potentially metalliferous shale. The integrated database underscores a potentially rapid mineralizing system of Late Mississippian (343-330 Ma) age. Evidence for isotopic exchange brings a Permo-Pennsylvanian (250-300 Ma) age derived from lead isotope modeling into question.Minor syndepositional mineralization is characterized by Fe oxide stained omission surfaces within well-oxidized hyposaline lithofacies, possibly documenting incipient hydrothermal activity, and subsequent marcasite mineralization related to introduction of hydrothermal (60 degrees - 120 degrees C) brines into a very restricted hyposaline or lacustrine setting during faulting. Prominent Zn-Pb sulfides (sphalerite, galena) and subsequent Ba-Sr sulfates (barite, celestite), with intergrown marcasite and calcite, have a shallow burial (30 + m) origin. Fluids were variably hot (110 degrees - 190 degrees C), Mg-poor brines (20-25 wt % NaCl equiv). Pyrite gossans mark a last stage of mineralization. The delta 34 S values increase with the general successon of sulfide (-4 to 12ppm), sulfate (20-32ppm), and then pyrite (32ppm) mineralization, similar to a Rayleigh distillation process in a closed mineralizing system.Mineralization on the Port au Port Peninsula is similar to Mississippian-hosted Irish Zn-Pb deposits; there is an association with normal faults, prominent epigenetic mineralization, and a similar age. This commonality may reflect Late Mississippian tectonic instability within the paleohemispheric fault system that linked eastern Canada and Ireland.