Relatively little is known about the mineralogical occurrence and geochemical controls on the incorporation of “invisible” (refractory) silver and gold in hydrothermal sulfide minerals. Secondary ion mass spectrometry (SIMS) analysis reveals that bornite (81–649 ppm Ag) and chalcopyrite (0.61–2211 ppm Ag) are major hosts for silver in the Mantos Blancos deposit (500 Mt, @1 wt% Cu), the largest Jurassic stratabound Cu-(±Ag) deposit in the Costal Range of northern Chile. Gold concentrations are generally two orders of magnitude lower, ranging from 0.05 to 1.66 ppm Au in chalcopyrite, and 0.08 to 2.38 ppm Au in bornite. In addition to precious metals, SIMS analysis shows significant concentrations of As (~100 ppm in chalcopyrite, <10 ppm in bornite), whereas other metalloids and chalcogens, such as Sb, Se, and Te, have highly variable concentrations ranging from tens of ppb to ppm levels. These microanalytical results are consistent with a two-stage hydrothermal evolution model, as recently proposed for the Mantos Blancos deposit. Within this context, Ag, Au, As, and base metals were most likely sourced from a Late Jurassic (~155 Ma) rhyolitic dome, and partitioned into bornite and chalcopyrite in quartz-sericite veins after cooling below ~430°C. This first hypogene Cu-Ag ± Au event was followed by a second, higher-temperature alteration phase (400–600 °C) related to the emplacement of diorite and granodiorite stocks (~141–152 Ma), in which Ag and Au were partitioned into fine-grained, porous chalcopyrite in potassic alteration vein assemblages. When coupled with recent studies in the area, results presented here confirm that the high Ag endowment of Mantos Blancos is the result of multiple pulses of hypogene mineralization followed by supergene enrichment of metals.