The human tissue inhibitor of metalloproteinases-3 (TIMP3) gene is the most recently characterized member of a family of genes whose products are implicated in extracellular matrix (ECM) remodelling. We previously described an increase in expression of TIMP3 mRNA in retinas affected by the progressive photoreceptor degenerative disease, simplex retinitis pigmentosa (RP). To gain further insight into the association between TIMP3 overexpression and retinal degeneration, we have analyzed the cellular localization of TIMP3 mRNA in control and simplex RP retinas using in situ hybridization. No TIMP3 mRNA expression was detectable in control neural retina. IN RP-affected retinas, overexpression of TIMP3 mRNA was observed in photoreceptor inner segments and in the ganglion cell layer only in those regions retaining relatively nondystrophic retinal architecture. Modulation of TIMP3 expression in these regions, possibly in association with matrix metalloproteinases, may reflect remodelling of the retinal ECM and concomitant reorganization of neuronal connectivity.