A 5-month-old boy presented with a right retrolental mass and glaucoma. Both B-scan ultrasonography and CAT scanning failed to disclose any evidence of intralesional calcification, the absence of which is unusual for retinoblastoma. An aqueous lactic dehydrogenase (LDH) determination disclosed elevated levels of this enzyme, which were six times that detected in the blood. Pathologic examination of the enucleated globe revealed rubeotic glaucoma, and a massively necrotic retinal tumor that had filled the vitreous cavity. A small focus of viable tumor in the posterior pole of the lesion displayed a population of rounded astrocytic giant cells, with abundant eosinophilic cytoplasm and eccentrically placed vesicular nuclei possessing prominent nucleoli. The cytoplasm of these tumors cells contained a moderate number of PTAH-positive fibrils, and these were identified positively as glial in nature by immunoperoxidase reaction for the presence of glial fibrillary acidic protein (GFAP). Mueller cells in a portion of surviving retina also stained positively for GFAP. Electron microscopic studies performed on a rim of surviving tumor cells abutting the subretinal space demonstrated features consistent with a Mueller cell origin, namely, abundant profiles of smooth and rough-surfaced endoplasmic reticulum and elaborate villous processes, the latter being typically produced by Mueller cells as they project beyond the external limiting membrane of the retina.