Computational models predict that focal damage to the Default Mode Network (DMN) causes widespread decreases and increases of functional DMN connectivity. How such alterations impact functioning in a specific cognitive domain such as episodic memory remains relatively unexplored. Here, we show in patients with unilateral medial temporal lobe epilepsy (mTLE) that focal structural damage leads indeed to specific patterns of DMN functional connectivity alterations, specifically decreased connectivity between both medial temporal lobes (MTLs) and the posterior part of the DMN and increased intrahemispheric anterior–posterior connectivity. Importantly, these patterns were associated with better and worse episodic memory capacity, respectively. These distinct patterns, shown here for the first time, suggest that a close dialogue between both MTLs and the posterior components of the DMN is required to fully express the extensive repertoire of episodic memory abilities.