The Collahuasi district is a porphyry Cu-Mo subprovince located on the Andean high plateau of northern Chile. Late Eocene-early Oligocene mineralization in the district involved hydrothermal alteration of the upper Paleozoic to Lower Triassic Collahuasi Group granodiorites, diorites, andesites, dacites, and rhyolites, which had previously experienced regional lower greenschist facies metamorphism as well as uneconomic porphyry-style mineralization and associated sericitic alteration. Alteration mapping represents an effective technique for prospecting for hydrothermal deposits, but, in low-grade metamorphic terrains, recognition of propylitic assemblages that represent the boundary of the mineralizing system is hampered by their resemblance to metamorphic mineral assemblages. Our results from Collahuasi indicate that petrographic criteria can distinguish propylitic alteration from the effects of lower greenschist facies metamorphism, but distinctions vary with rock type. Mafic, intermediate, and felsic rocks with varying degrees of propylitic alteration can be distinguished from background metamorphism mainly by the presence of calcite. However, propylitic alteration can also be distinguished by high whole-rock δ 13C values and carbon contents (−19.1 to −1.4‰ and up to 0.79 wt %, respectively) that result from the incorporation of magmatic CO2 during the mineralizing events. Lower δ 13C values (−32.7 to −13.1‰) and carbon contents (<0.09 wt %) were recorded in other types of hydrothermal alteration (intermediate argillic, sericitic, and potassic alteration) and associated with background metamorphism. They reflect a dominantly 13C depleted carbon component that remains in the rocks after extensive CO2 degassing during emplacement, alteration by hydrothermal fluids, or contamination by organic carbon. Carbon and oxygen isotope compositions of calcite from propylitic alteration, which range from −12 to +0.3‰ and 6.6 to 25.9‰, respectively, are consistent with a predominantly magmatic origin for the carbonates, although subsequent resetting of the oxygen isotopes by local ground water and minor contributions of organic carbon are recorded in some samples. Spatial variation in δ 13C values and carbon contents of outcrop samples from the Collahuasi district delineate zones of high magmatic CO2 component that correspond exclusively to propylitic alteration surrounding economic deposits.