High field strength elements (HFSE), especially Nb, Ta, and Ti, are commonly considered to be immobile during fluid-rock interaction in ore-forming systems. Hence the mechanisms behind their migration and fractionation associated with mineralization are not often studied. Here, we present a research study of different generations of Nb-Ta-bearing hydrothermal rutile at the giant Qulong porphyry Cu-Mo deposits, Gangdese magmatic belt, Xizang. Based on mineral assemblages and elemental compositions, two distinct groups of rutile can be identified: (1) coarse-grained Rt-1 is found in quartz-biotite-anhydrite veins. It is characterized by high Nb, Fe, Cr, and W contents and formed from the mobilization of HFSE in a relatively oxidized, metal-rich, hypersaline brine during the early high-temperature potassic alteration stage. These rutile grains exhibit suprachondritic Nb/Ta ratios from 20 to 80, that are higher than those of primitive mantle. This may be attributed to the high solubility of HFSE in hypersaline brines, which favors a fractionation of Nb over Ta. (2) Abundant, disseminated, blocky Rt-2 is hosted in monzogranite and monzonitic porphyry, where it forms intergrowths with sericite, chlorite, pyrite, and chalcopyrite. It has relatively low Nb/Ta ratios and formed by alteration of precursor Ti minerals, such as biotite and titanite, during sericite and chlorite alteration stages. This indicates that this generation of rutile was precipitated, together with the ore-forming elements, from moderate-temperature, aqueous fluids. The Nb/Ta variations between the two generations of rutile, reflect the evolution of the mineralizing fluids from an early relatively oxidized, halogen-alkaline-rich composition to late less saline, moderate-temperature fluids. Both Rt-1 and Rt-2 crystallized in these different fluid settings yield 206Pb/238U ages of 16.50 ± 0.32 Ma to 14.70 ± 0.30 Ma, that record the timing of rutile growth and reflect the extended duration of HFSE mobility and final Cu-Mo mineralization. These results suggest that the mobilization and fractionation of HFSE is more common during mineralization in magmatic-hydrothermal metallogenetic systems than often observed, and may thus help elucidate the fluid evolution of magmatic-hydrothermal metallogenetic systems and aid mineral exploration.