The studied sulfide mineralizations of Atshan and Darhib areas are related to the south Eastern Desert shear zones. They are hosted in talc- and tremolite-talc-rich rocks and also in meta-basaltic dykes and quartz-veins. The principal mineralization in Atshan includes sphalerite, pyrite, chalcopyrite, galena and pyrrhotite, whereas that in Darhib comprises chalcopyrite, sphalerite, pyrite, and galena with subordinate bornite and covellite. Darhib mineralization contains traces of altaite and electrum. Altaite has the highest Te concentrations suggesting crystallization under low fS2 and/or high fTe2 conditions, probably due to S budget consumption from the hydrothermal fluids in the late stage of deposition. Electrum has the highest Au contents with gold fineness value falling within the range of epithermal Au–Ag deposits. The dominance of recrystallized and replacement textures in the studied mineralizations suggests a secondary or post-depositional metamorphic overprint. The significant Cd contents in sphalerite from remobilized massive mineralizations hosted in tremolite-talc-rich rocks indicate crystallization at ~250–300 °C. Galena hosted in tremolite-talc-rich rocks is characterized by exceptionally high selenium and tellurium contents, indicating its generation from relatively Se–Te-enriched hydrothermal fluids. Pyrrhotite hosted in quartz-veins from Atshan was formed under lower sulfur activity (aS2) and oxygen fugacity (fO2). Covellite and bornite were formed due to chalcopyrite oxidation, revealing a role of supergene process. Shear zones, possibly produced during later thrust faulting, were acted as channel ways for hydrothermal mineralizing fluids that may have modified and/or precipitated the mineralization. Mineralizing fluids have probably resulted from dehydration during metamorphism and/or late-magmatic fluids from nearby granitic intrusions.