The capacity to respond to novel events is crucial for adapting to the constantly changing environment. Here, we recorded 29-channel Event Related Brain Potentials (ERPs) during an active auditory novelty oddball paradigm and used for the first time Current Source Density-transformed Event Related Brain Potentials and associated time-frequency spectra to study target and novelty processing in a group of epileptic patients with unilateral damage of the hippocampus (N = 18) and in healthy matched control participants (N = 18). Importantly, we used Voxel-Based Morphometry to ensure that our group of patients had a focal unilateral damage restricted to the hippocampus and especially its medial part. We found a clear deficit for target processing at the behavioral level. In addition, compared to controls, our group of patients presented (i) a reduction of theta event-related synchronization (ERS) for targets and (ii) a reduction and delayed P3a source accompanied by reduced theta and low-beta ERS and alpha event-related synchronization (ERD) for novel stimuli. These results suggest that the integrity of the hippocampus might be crucial for the functioning of the complex cortico-subcortical network involved in the detection of novel and target stimuli.