We have studied the effects on the chick embryo's isthmo-optic nucleus of de-efferentation alone or in combination with deafferentation. De-efferentation was achieved by pharmacological destruction of the axonal target cells in the retina at E13, or by colchicine-blockade of axoplasmic transport in the intraocular parts of the isthmo-optic axons at E13; deafferentation was by a tectal lesion at E11 or E12. De-efferentation alone causes all the isthmo-optic neurons to die, and mostly by the "endocytic-autophagic" mode of cell death, which is characterized by pronounced endocytosis (of an intravascularly injected label) and by intense, clumped activity of two lysosomal enzymes (acid phosphatase and N-acetyl-beta-glucosaminidase). Deafferentation plus de-efferentation caused there to be less endocytic-autophagic dying cells in the isthmo-optic nucleus than after de-efferentation alone, but all the neurons still died. Our interpretation is that deafferentation switched many of the isthmo-optic neurons to a completely different (nonendocytic, nonautophagic) mode of cell death.