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Purpose Orange pigment is an important sign of malignancy in melanocytic tumors. There is a question as to whether the pigment accumulation is inside of macrophages or retinal pigment epithelial (RPE) cells. We investigated which cells are involved with this color alteration. Methods We examined enucleated specimens from two patients with choroidal melanoma and dense orange pigment on fundus examination. Color fundus and fundus autofluorescence (FAF) photographs were reviewed followed by examination with fluorescent microscopy, electron microscopy, and immunohistochemistry of enucleated eyes for the specific areas corresponding to the orange pigment. Results Orange pigment was observed on color fundus photography and correlated with areas of hyperautofluorescence on FAF. Fluorescent microscopy of sections of the enucleated eyes showed autofluorescence in the RPE, which were most pronounced where there was a localized retinal detachment and reactive hyperplasia of the RPE. Immunohistochemical studies were done with keratin (OSCAR and AE1/AE3) and S-100 stained RPE cells, which still were attached to Bruch's membrane. Histiocytes present in the detached retina stained with anti-CD163 antibody and did not show autofluorescence. Electron microscopy studies of the same areas showed the presence of lipofuscin and melanolipofuscin within the clustered RPE cells. Conclusions Orange pigment in choroidal melanocytic lesions originates from the RPE cells, rather than macrophages, and is most abundant where there is proliferation of the RPE. Translational Relevance The orange pigment tumoral biomarker arises and is in the retinal pigment epithelium.