A time series of the physical and biogeochemical properties of Subantarctic Mode Water (SAMW) and Antarctic Intermediate Water (AAIW) in the Drake Passage between 1969 and 2005 is constructed using 24 transects of measurements across the passage. Both water masses have experienced substantial variability on interannual to interdecadal time scales. SAMW is formed by winter overturning on the equatorward flank of the Antarctic Circumpolar Current (ACC) in and to the west of the Drake Passage. Its interannual variability is primarily driven by variations in wintertime air–sea turbulent heat fluxes and net evaporation modulated by the El Niño–Southern Oscillation (ENSO). Despite their spatial proximity, the AAIW in the Drake Passage has a very different source than that of the SAMW because it is ventilated by the northward subduction of Winter Water originating in the Bellingshausen Sea. Changes in AAIW are mainly forced by variability in Winter Water properties resulting from fluctuations in wintertime air–sea turbulent heat fluxes and spring sea ice melting, both of which are linked to predominantly ENSO-driven variations in the intensity of meridional winds to the west of the Antarctic Peninsula. A prominent exception to the prevalent modes of SAMW and AAIW formation occurred in 1998, when strong wind forcing associated with constructive interference between ENSO and the southern annular mode (SAM) triggered a transitory shift to an Ekman-dominated mode of SAMW ventilation and a 1–2-yr shutdown of AAIW production. The interdecadal evolutions of SAMW and AAIW in the Drake Passage are distinct and driven by different processes. SAMW warmed (by 0.3°C) and salinified (by 0.04) during the 1970s and experienced the reverse trends between 1990 and 2005, when the coldest and freshest SAMW on record was observed. In contrast, AAIW underwent a net freshening (by 0.05) between the 1970s and the twenty-first century. Although the reversing changes in SAMW were chiefly forced by a 30-yr oscillation in regional air–sea turbulent heat fluxes and precipitation associated with the interdecadal Pacific oscillation, with a SAM-driven intensification of the Ekman supply of Antarctic surface waters from the south contributing significantly too, the freshening of AAIW was linked to the extreme climate change that occurred to the west of the Antarctic Peninsula in recent decades. There, a freshening of the Winter Water ventilating AAIW was brought about by increased precipitation and a retreat of the winter sea ice edge, which were seemingly forced by an interdecadal trend in the SAM and regional positive feedbacks in the air–sea ice coupled climate system. All in all, these findings highlight the role of the major modes of Southern Hemisphere climate variability in driving the evolution of SAMW and AAIW in the Drake Passage region and the wider South Atlantic and suggest that these modes may have contributed significantly to the hemispheric-scale changes undergone by those waters in recent decades.