A biogeochemical ocean general circulation model, driven with NCEP-R1 and observed atmospheric CO2 history, is used to investigate and quantify the role that the Southern Annular Mode (SAM), identified as the leading mode of climate variability, has in driving interannual variability in Southern Ocean air-sea CO2 fluxes between 1980 and 2000. Our simulations show the Southern Ocean to be a region of decreased CO2 uptake during the positive SAM phase. The SAM induces changes in Southern Ocean CO2 uptake with a 2-month time lag explaining 42% of the variance in the total interannual variability in air-sea CO2 fluxes. Our analysis shows that the response of the Southern Ocean to the SAM is primarily governed by changes in ΔpCO2 (67%), and that this response is driven by changes in ocean physics that control the supply of nutrients to the upper ocean, primarily Dissolved Inorganic Carbon (DIC). The SAM is predicted to become stronger and more positive in response to climate change and our results suggest this will decrease the Southern Ocean CO2 uptake by 0.1PgC/yr per unit change in the SAM.