The oxygen and hydrogen isotope composition of hydrothermal fluids associated with the Variscan granites of southwest England has been inferred from analysis of various silicate minerals (predominantly quartz) and by direct analysis of fluid inclusions within quartz and fluorite. These data have been combined with the results of a fluid inclusion study to develop a model for the origin and evolution of hydrothermal fluids in the region. Magmatic fluids expelled from the granites had compositions in the range δD = −65 to −15‰, and δ¹⁸O = 9 to 13‰. Respective temperature, salinity, fluid δD, and fluid δ¹⁸O values for the (i) early Sn-W mineralization, (ii) later Cu-Pb-Zn sulphide mineralization, and (iii) latest ‘crosscourse’ Pb-Zn-F mineralization are: (i) 230–400 °C, 5–15 wt.% NaCl equiv., −39 to −16‰, and 7.0 to 11.2‰, (ii) 220–300 °C mostly 2–8 wt.% NaCl equiv., −41 to −9‰, and 2.3 to 8.1‰, and (iii) 110–150 °C 22–26 wt.% NaCl equiv., −45 to +2‰, and −1.8 to +5.5‰. These data highlight the important role of both magmatic fluids exsolved from the crystallizing granite, and basinal brines circulating within restricted fracture systems.