Changes in ocean circulation have been proposed as a trigger mechanism for the large coupled climate and carbon cycle perturbations at the Paleocene-Eocene Thermal Maximum (PETM, ca. 55 Ma). An abrupt warming of oceanic intermediate waters could have initiated the thermal destabilization of sediment-hosted methane gas hydrates and potentially triggered sediment slumps and slides. In an ensemble of fully coupled atmosphere-ocean general circulation model (AOGCM) simulations of the late Paleocene and early Eocene, we identify such a circulation-driven enhanced intermediate-water warming. Critically, we find an approximate twofold amplification of Atlantic intermediate-water warming when CO2 levels are doubled from 2× to 4× preindustrial CO2 compared to when they are doubled from 1× to 2×. This warming is largely focused on the equatorial and South Atlantic and is driven by a significant reduction in deep-water formation from the Southern Ocean. This scenario is consistent with altered PETM circulation patterns inferred from benthic carbon isotope data and the intensity of deep-sea carbonate dissolution in the South Atlantic. The linkage between intermediate-water warming and gas hydrate destabilization could provide an important feedback in the establishment of peak PETM warmth.