We have previously demonstrated with histochemical digestions that a spatial heterogeneity exists in the interphotoreceptor matrix (IPM) of the normal rat retina. The apical outer segment zone adjacent to the pigment epithelium is mostly sialoglycoconjugates, and the basal outer segment zone appears to consist largely of chondroitin sulfates A and C, with sialogylcoconjugates in low concentration (Porrello and LaVail, in press). Although the RCS rat with inherited retinal dystrophy is missing the apical zone of IPM in the posterior retina, it has an abnormally high concentration of IPM in the basal zone and a concentrated apical zone in the far peripheral retina (LaVail, Pinto and Yasumura, 1981). We have attempted to characterize the IPM histochemically in these two regions in the RCS rat. Using the same digestive procedures which remove hyaluronic acid, chondroitin sulfates A and C, and sialoglycoconjugates, we find that the excessive basal IPM accumulation in the RCS retina appears to be composed in large part of chondroitin sulfates A and C, whereas the peripheral apical zone contains little or no chondroitin sulfates A and C. Furthermore, little or no sialoglycoconjugates are present in the basal zone, and the peripheral apical zone is composed predominantly of sialoglyconjugates. Thus, the IPM in the RCS rat possesses the same regional heterogeneity as that found in the normal rat IPM. Changes in IPM staining during the progression of retinal degeneration were examined in the eyes of both pink-eyed RCS and pigmented RCS-p+ rats. IPM staining was characterized by progressive condensation of the initially abundant basal stain into a thin band adjacent to the outer limiting membrane. The loss was concomitant with the reduction in photoreceptor inner-segment length and integrity, precisely matching the central to peripheral gradient and hemispheric differences in the rate of photoreceptor degeneration in these animals. This suggests that photoreceptor cells produce some or all of the chondroitin sulfates of the IPM. The peripheral apical staining was lost rapidly between days 30-40, which correlates closely with the loss of interstitial retinol-binding protein as described by others.