Rationale: Patients with medial temporal lobe epilepsy (MTLE) commonly present with declarative memory deficits, whereas semantic memory and other functions remain relatively intact. The circuit-level dysfunction contributing to this specific memory impairment remains unknown. We recorded from individual human neurons from inside and outside the seizure onset zone (SOZ) in patients with unilateral MTLE to assess whether the properties of functionally distinct types of neurons involved in declarative memory formation differ within the epileptic medial temporal lobe. Methods: Forty patients with intractable epilepsy underwent hybrid depth electrode implantation for seizure localization. Subjects performed a recognition memory task with confidence ratings while we recorded the activity of single neurons using microwires in the amygdala and the hippocampus. We characterized the properties of different functional cell types known to be involved in declarative memory: visually selective (VS), animal responsive (AR), and memory selective (MS) neurons (Rutishauser et al., 2015). We compared the tuning properties of these neurons using the depth of selectivity (DOS) index and ROC analysis to assess whether the response properties of neurons located within the seizure onset zone (SOZ) differed and whether these differences were of relevance to memory dysfunction. Results: Out of the 1,573 recorded neurons, we identified 336 VS, 270 AR, and 123 MS neurons. The tuning strength (assessed by DOS) of the VS neurons did not differ significantly between neurons within vs. outside the SOZ in both the amygdala and hippocampus (p=0.35 and p=0.63, respectively). In contrast, the tuning strength of AR neurons located inside the SOZ was significantly reduced in the amygdala (0.18 vs. 0.29, p=0.001) but not the hippocampus (0.18 vs. 0.17, p=0.90). This deficit was selective to animal-responsive neurons. The response of MS neurons differentiated between novel and familiar stimuli significantly less strongly inside the SOZ in both amygdala and hippocampus (DOS 0.24 vs. 0.32, p=0.01). This deficit was particularly pronounced during trials in which subjects recognized a stimulus with high confidence (normalized firing rate 1.21 vs. 1.61, p=0.02). Strikingly, MS neurons lost the ability to differentiate between high and low confidence memories within but not outside the SOZ. Conclusions: The response of MS neurons within the SOZ was significantly altered in two ways: reduced ability to differentiate between familiarity and novel stimuli, and inability to distinguish between items retrieved with high and low confidence. In contrast, the tuning strength of VS neurons within the SOZ was indistinguishable from that of neurons outside the SOZ. This data thus reveals a selective memory dysfunction at the single neuron level within the SOZ, a finding that indicates a reason for the specificity of the episodic memory impairment observed in patients with MTLE relative to other functions that are also dependent on the MTL. The response of amygdala neurons to animals was also disrupted inside the SOZ, further supporting the amygdala’s hypothesized role in the detection of animals (Mormann et al., 2011). We hypothesize that the functional activity impaired by MTLE may represent signals computed locally, whereas the signals unaffected by MTLE are passed on from upstream areas, thereby not suffering from local disruption. Funding: Please list any funding that was received in support of this abstract.: Grant supported by the NIMH (R01MH110831) and NINDS (U01NS103792, U01NS098961) to UR.