Mullerian glia in retinas of Royal College of Surgeons (RCS) dystrophic rats and retinal degeneration (rd/rd) mice undergo biochemical and morphological alterations concomitant with photoreceptor loss. To follow the fate of Mullerian glia in these degenerating retinas, two Muller cell-specific markers, carbonic anhydrase-C (CAC) and cellular retinaldehyde-binding protein (CRALBP), were examined by light microscopic immunocytochemistry. In retinas of 1- to 12-month-old RCS dystrophic rats, cell bodies in the inner nuclear layer and radial processes were immunostained for CAC, but appeared to diminish with age. In addition, a material in the region of the retinal pigment epithelium (RPE), representing expansion of Muller cell processes into the subretinal space, was immunolabelled for CAC in retinas of 2-month-old and older RCS rats. The CAC-immunoreactive Muller cells seen in retinas of 12-month-old RCS rats were disorganized, as significant photoreceptor degeneration had occurred by this time. In retinas of 6-week-old RCS rats, Muller cells and their processes were immunolabelled for CRALBP, which spanned from the nerve fiber layer (NFL) through the outer nuclear layer. The density of this immunostaining increased, especially in the subretinal space, with advancing age in RCS rats, seen most prominently in retinas of 9-month-old RCS rats and decreased by 12 months. In retinas of rd/rd mice beginning by day 14, minimal CAC- and CRALBP-immunoreactive material was observed in the subretinal space. By 6 weeks, when a majority of the photoreceptors had degenerated, the CAC-staining pattern appeared significantly reduced and patchy. This study showed that Muller cells in degenerating retinas of RCS rats and rd/rd mice ultimately exhibited decreased immunolabelling for CAC and CRALBP at the more advanced stages of retinopathy, which coincided with the loss of photoreceptors. This is in contrast to the progressive increase in glial fibrillary acid protein (GFAP), an intermediate filament protein, throughout the retinal dystrophy in both animal models.