Porphyry Cu-Mo deposits (PCDs) are the world’s major source of Cu, Mo, and Re and are also a significant source of Au and Ag. Here we focus on the world-class Río Blanco PCD in the Andes of central Chile, where Ag is a by-product of Cu mining. Statistical examination of an extensive multielemental inductively coupled plasma-mass spectrometry data set indicates compositional trends at the deposit scale, including Ag-Cu (r = 0.71) and Ag-In (r = 0.53) positive correlations, which relate to Cu-Fe sulfides and Cu sulfosalts in the deposit. Silver is primarily concentrated in Cu ores in the central core of the deposit, and significant variations in the Ag concentration are related to the different hydrothermal alteration types. The concentration of Ag is highest in the potassic core (avg 2.01 ppm) and decreases slightly in the gray-green sericite (phyllic) zone (avg 1.72 ppm); Ag is lowest in the outer propylitic alteration zone (avg 0.59 ppm). Drill core samples from major hydrothermal alteration zones were selected for in situ analysis of Ag and associated elements in sulfide and sulfosalt minerals. To ensure representativeness, sample selection considered the spatial distribution of the alteration types and ore paragenesis. Chalcopyrite is the most abundant Cu sulfide in Río Blanco, with Ag concentration that ranges from sub-parts per million levels to hundreds of parts per million. The highest concentration of Ag in chalcopyrite is associated with the high-temperature potassic alteration stage. Bornite is less abundant than chalcopyrite but has the highest Ag concentration of all studied sulfides, ranging from hundreds of parts per million up to ~1,000 ppm. The Ag concentration in bornite is higher in lower-temperature alteration assemblages (moderate gray-green sericite), opposite to the behavior of Ag in chalcopyrite. Pyrite has the lowest Ag content, although concentrations of other critical elements such as Co, Ni, and Au may be significant. The highest Ag concentrations, i.e., thousands of parts per million up to weight percent levels, were detected in late-stage Cu sulfosalts (enargite, tennantite, and tetrahedrite). The Ag content in these sulfosalts increases with increasing Sb concentrations, from the Sb-poor enargite to the Sb-rich tetrahedrite. The earliest Ag mineralization event is related to the potassic alteration stage represented by early biotite and transitional early biotite-type veinlets and where the predominant sulfides are chalcopyrite and bornite. Silver mineralization during this stage was predominantly controlled by crystallization of Cu-Fe sulfides. The second Ag mineralization event at Río Blanco is associated with the transitional Cu mineralization stage, which is represented by the gray-green sericite alteration (C-type veinlets). In this alteration type, Ag was partitioned preferentially into chalcopyrite, bornite, and to a lesser extent pyrite. The last Ag mineralization event is related to the late quartz-sericite alteration stage, characterized by D- and E-type veinlets with pyrite-chalcopyrite and enargite-tennantite-tetrahedrite. Our data indicate that Ag was associated with several Cu mineralization episodes at Río Blanco, with Ag concentration apparently controlled by cooling, changes in pH, fO2 and fS2 of the hydrothermal fluids, and the intensity of alteration. Overall, our results provide information on critical metal partitioning between sulfides, plus the distribution of critical element resources at the deposit scale. Knowledge of the mineralogical occurrence of critical metals in PCDs is necessary to better assess their resources and evaluate the potential for their recovery.