Objective: Although the hippocampus is critical for memory processes, recent studies have suggested that amnesic patients with hippocampal lesions can still acquire some types of memory by distributed learning rather than by massed learning. However, as these studies recruited patients with developmental amnesia, whether lesion onset influenced the spacing effect was unclear. In addition, the extent to which the prefrontal cortex (PFC) supports the spacing effect has not been explored. Method: Patients with hippocampal lesions at early onset and late onset and PFC lesions were enrolled. The participants learned face-scene pairs under single learning (i.e., once in 1 day), massed learning (i.e., four times in 1 day), and distributed learning (i.e., four times in 2 days, twice per day). Then, they performed associative recognition tasks 20 min and 1 day later. Results: The results showed that the spacing effect was significantly higher than baseline (d = 2.91) and comparable with the control groups for hippocampal lesions at early onset patients at 1 day. However, the spacing effect was significantly impaired for hippocampal lesions at late onset (d = -1.84) and PFC patients (d = -1.48) when compared with the normal groups. The repetition effect (massed vs. single learning) was significantly impaired for PFC patients at 20 min when compared with the controls (d = -1.15). Conclusions: These findings clarified the roles of the hippocampus and PFC in distributed learning and repetitive learning and suggest that early-onset hippocampal damage induces a significant reorganization in the human brain to support memory formation and retention.