Purpose: Retinal detachment induces Muller cell hypertrophy both within the retina and as cellular membranes in the subretinal space. Structural and immunolabeling data suggest a prominent role for the cytoskeleton in this process. Indeed, glial fibrillary acidic protein (GFAP), vimentin, and tubulin upregulation are all hallmarks of the hypertrophy. There also may be a relationship between Muller cell hypertrophy and neuronal remodeling after detachment. Here we sought to determine if Muller cell hypertrophy was functionally dependent upon the presence of the 2 intermediate filament proteins GFAP and vimentin. Methods: Experimental retinal detachments were created in wild-type C57BL/6J mice and mice deficient in GFAP and vimentin (GFAP-/-vim-/-). The retinas were harvested at 7 or 28 days post-detachment. Immunohistochemistry was performed using antibodies to GFAP, vimentin, S100, VAMP, rod opsin, cone opsins, protein kinase C, and neurofilament protein. Images were collected with an Olympus Fluoview confocal microscope. Results: Glial cell hypertrophy was observed in both wild-type and GFAP-/-vim-/- mice following detachment. Focal regions of Muller cell growth appeared sclerad to the outer limiting membrane in both groups after detachment. These processes were anti-GFAP, -S100, and -vimentin labeled in wild-type mice and only anti-S100 labeled in the GFAP-/-vim-/-. Anti-S100 labeling revealed abnormal Muller cell morphology in the attached GFAP-/- vim-/- retina, which was exaggerated after detachment. Extensive neuronal remodeling also occurred both in the GFAP-/-vim-/- and wild-type animals. These events included the sprouting of neurites from bipolar and horizontal cells into the outer nuclear layer. Conclusions: These studies demonstrate that the intermediate filament proteins GFAP and vimentin are not required for the hypertrophy of Muller cells nor does their absence prevent neuronal remodeling/sprouting in the GFAP-/-vim-/- retinas. The results suggest that other cytoskeleton protein(s) may play a critical role in initiating Muller cell hypertrophy.