Consolidated memories return to a labile state after the presentation of cues (reminders) associated with acquisition, followed by a period of stabilization (reconsolidation). However not all cues are equally effective in initiating the process, unpredictable cues triggered it, predictable cues do not. We hypothesize that the different effects observed by the different reminder types on memory labilization-reconsolidation depend on a differential neural involvement during reminder presentation. To test it, we developed a declarative task and compared the efficacy of three reminder types in triggering the process in humans (Experiment 1). Finally, we compared the brain activation patterns between the different conditions using functional magnetic resonance imaging (fMRI) (Experiment 2). We confirmed that the unpredictable reminder is the most effective in initiating the labilization-reconsolidation process. Furthermore, only under this condition there was differential left hippocampal activation during its presentation. We suggest that the left hippocampus is detecting the incongruence between actual and past events and allows the memory to be updated.