Purpose. To determine whether retinal pigment epithelium (RPE) in eyes with age-related macular degeneration (ARMD) express vimentin and α smooth muscle actin (αSMA), two cytoskeletal proteins associated with phenotypic variation in culture. Methods. Six eyes with late ARMD and three age-matched control eyes were preserved in buffered 4% paraformaldehyde and cryosectioned at 10 μm. Stages of RPE morphology and pigmentation were assessed by the Alabama Age-Related Macular Degeneration Grading System. Vimentin, αSMA, and glial fibrillary acidic protein (GFAP) expression was detected by indirect immunofluorescence. These results were compared with regional variations in disease severity. Results. RPE changes in ARMD included acquired expression of vimentin, but αSMA-positive cells were rare. GFAP expression increased in Müller cells in the neural retina in association with RPE changes and photoreceptor degeneration. Conclusions. The initial stages of RPE changes in eyes with ARMD mimic those reported for cultured RPE cells. The absence of αSMA-positive cells in regions of RPE atrophy suggests that RPE are lost rather than persist in a dedifferentiated state.