The Fetal ALZ-50 Reactive Clone 1 (FAC1) gene is expressed at high levels during brain development and is re-expressed in some neurodegenerative diseases. It is hypothesized that FAC1 functions during neuronal differentiation and may play an active role in neuritic re-organization following brain injury. We have previously employed the entorhinal cortex lesion model to examine reactive synaptogenesis and plasticity in the hippocampal dentate molecular layer following denervating lesion. We now report re-expression of FAC1 in the molecular layer (ML) of the dentate gyrus following entorhinal cortex (ERC) lesion. Denervated hippocampi (2,6,15, and 30 days post ERC lesion) were stained with anti-FAC1 antibody and processed for both light and electron microscopy. FAC1 was rapidly re-expressed (by 2 days) following ERC lesion, paralleling our previous observations with embryonic neural cell adhesion molecule (eN-CAM). Like eN-CAM, FAC1 expression was restricted to the denervated outer ML (OML) at 2 days post lesion. Analysis of later time points revealed an elimination of FAC1 immunostaining at the inner ML (IML)/(OML) interface as IML sprouts into the denervated zone. Image analysis confirmed the diminution of FAC1 staining in the OML as the IML sprouted into the denervated zone and revealed that FAC1 expression paralleled the temporal and spatial expression of eN-CAM following ERC lesion. Ultrastructural analysis of FAC1 staining at 6 and 30 days post lesion revealed immunoreactive profiles with the morphological characteristics of dendrites and cytoplasmic staining of granule cell perikarya. Dendritic staining was localized to the denervated OML and was not associated with any other neuropil profiles within this zone; IML staining was rare and restricted to large apical dendrites proximal to granule cell perikarya. These findings suggest that re-expression of FAC1 in the denervated OML is a rapid response to brain injury and may be important in synaptic plasticity and sprouting.