True neoplasms can arise from pigment epithelium of the iris, ciliary body, and retina (retinal pigment epithelium [RPE]).1-4 We report a large adenocarcinoma of RPE that was a diagnostic challenge based on clinical features, cytopathology, and immunohistochemistry. However, with routine histopathology of the enucleated eye, the diagnosis of RPE adenocarcinoma was established.