The Rouyn-Noranda mining district of Quebec contains 20 Cu-Zn (±Au ±Ag) volcanogenic massive sulfide (VMS) deposits, including the giant and gold-rich Quemont and Horne deposits. Mineralized epigenetic veins are also present, but their origin and relative timing remain enigmatic. The nature and extent of their alteration signatures and the effect of their superposition on district-scale alteration patterns is unknown. The VMS-related quartz-sulfide Cu-Zn-Ag veins have δ18Oquartz values of 8.5 ± 0.8‰, reflecting δ18Ofluid compositions of –0.4 to 3.1‰ (250°–350°C) that are typical of Archean seawater. They are associated with a proximal Fe-rich chlorite alteration and marginal spotted sericite-chlorite alteration with whole-rock δ18O values of 2.9 to 5.9‰ and are interpreted to have formed within the structurally controlled discordant upflow zones of a VMS hydrothermal system. Younger gold-bearing quartz-carbonate veins were emplaced along mechanical anisotropies created by mafic dikes during north-south compression and the formation of regional E-trending faults, folds, and cleavage. They are characterized by δ18Oquartz values of 11.3 ± 0.8‰, reflecting δ18Ofluid compositions of 2.4 to 5.9‰ (250°–350°C), typical of a metamorphic fluid, possibly mixed with a lower δ18O upper crustal fluid. They are associated with ankerite, calcite, muscovite, chlorite, albite, and quartz ± hematite alteration with whole-rock δ18O values of 5.8 to 10.3‰. Chemical abrasion-isotope dilution-thermal ionization mass spectrometry (CA-ID-TIMS) U-Pb zircon ages for two tonalite intrusions constrain the maximum age of the Cu-Zn-Ag veins to 2697.6 ± 0.7 Ma and the minimum age to 2695.3 ± 1.0 Ma, which is also the maximum age of the gold quartz-carbonate veins. Superposition of alteration related to the gold quartz-carbonate veins on previously chlorite- and sericite-altered rocks has resulted in mixed alteration signals with whole-rock δ18O values of ~6 to 8‰ that have perturbed and masked regional alteration patterns related to older VMS mineralization, such as those found in the Quemont and Horne deposits. These results indicate that defining alteration vectors in camps that have superimposed hydrothermal systems requires full consideration of the hydrothermal history of the camp, and if such constraints are lacking, whole-rock δ18O values should not be used as a stand-alone exploration method.