Hypotheses concerning processes and timing of hydrothermal sulfide mineralization in the central Pennsylvanian Appalachians utilize Mississippi Valley-type (MVT) models with Paleozoic ages. To examine this model, we studied sulfide-bearing veins in the Skytop sulfide occurrence that contain pyrite<galena<sphalerite and occurs in central Pennsylvania, USA. In this study, we obtained Re's isotope compositions of hydrothermal pyrite and fluid inclusion data from hydrothermal quartz intergrown with these pyrites. Pyrite occurs in two separate structural domains as thin vein fillings and in a younger cross cutting fault breccia. Pyrite in both domains is intergrown with quartz and forms micron sized needles and whisker overgrowths on cubic and octahedral pyrite. The fault breccia pyrite contains more Re and Os, on average (6 ppb and 41 ppt) than the vein pyrite (2 ppb and 20 ppt). A seven point Re Os isochron from the fault breccia pyrite yielded an age of 33.8 ± 4.8 Ma and an 187Os/188Os initial ratio of 0.18 ± 0.05. None of the vein pyrite samples lie on this isochron. Fluid inclusion homogenization temperatures from quartz sampled near the fault range from 140 to >375 °C. The high temperature fluid inclusions occur within 5 feet of the fault. The Re-Os isotope and fluid inclusion data do not fit current models for sulfide generation in central Pennsylvania that invoke MVT hydrothermal processes. These MVT models imply that mineralization in the area formed in the late Paleozoic at relatively low temperatures (120 ± 40 ° C) with metals originating from surrounding sedimentary rocks. The data from the present study indicates that a younger, high temperature (>200 °C) mineralization event (represented by the fault breccia pyrite) overprinted the MVT type mineralization (represented by the vein pyrite). The timing of the younger mineralization event coincides with two Cenozoic events in the Appalachian Basin: the Chesapeake Bay impact and Eocene volcanism in the southern portion of the Nittany anticlinorium.