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Oxygen concentrations in the deep waters of the Lower St. Lawrence Estuary have decreased by 50% over the past century. The drivers of this decrease are investigated by applying an extended Optimum Multiparameter analysis to a time series of physical and biogeochemical observations of the St. Lawrence Estuarine System in the 1970s and from late 1990s to 2018. This method reconstructs the relative contributions of the two major water masses feeding the system, the Labrador Current Waters (LCW) and the North Atlantic Central Waters (NACW), as well as oxygen utilization, and accounts for diapycnal mixing. The causes of the oxygen decline varied over the last 5 decades. Between the 1970s and late 1990s, the decrease was mainly driven by biogeochemical changes through an increase in microbial oxygen utilization in the St. Lawrence Estuary in response to warmer temperatures and eutrophication …