The novelty of a cue may arise from the presence of an element that has not previously been experienced or from familiar elements that have been rearranged. The present study mapped the anatomical basis of responding to this second form of novelty. For this, rats were trained on a working memory spatial task in a radial-arm maze in a cue-controlled environment. On the final test day the positions of the familiar, extra-maze cues were rearranged for half of the rats (group Novel). The spatial configuration of the cues now matched that of the control rats (group Familiar). Neuronal activation, as measured by the immediate early gene, c-fos, was then compared between the two groups. Rearrangement of visual stimuli led to significant increases in Fos-positive cells in various hippocampal subfields (rostral CA1, rostral CA3 and rostral dentate gyrus) as well as the parietal cortex and the postsubiculum. In contrast, no changes were observed in other sites including the perirhinal cortex, postrhinal cortex, lateral and medial entorhinal cortices, retrosplenial cortices, or anterior thalamic nuclei. These results highlight the selective involvement of the hippocampus for processing novel rearrangements of visual stimuli and suggest that this involvement is intrinsic as it is independent of the parahippocampal cortices. This pattern of Fos changes is the mirror image of that repeatedly found for novel individual stimuli (perirhinal increase, no hippocampal change), demonstrating that these two forms of novelty have qualitatively different neural attributes.