Retinal pigment epithelium (RPE) plays an important role in retinal function, and may contribute to retinal degeneration via expression of specific cytokines. The retina of a four-vessel occlusion rat model was used to investigate the localization of TNF-α following ischemia/ reperfusion, to determine whether TNF-α expression may contribute to retinal degeneration. At the ultrastructural level, the 2-day RPE cells were irregular in shape, and showed increased phagocytosis of rod outer segments. Immunohistochemistry demonstrated that ischemia-damaged RPE cells showed upregulation of N-methyl-D-aspartate receptor type 1 ( NMDA-R 1) and TNF-α immunorea-ctivity. However the first appearance of NMDA-R 1 immunoreactivity preceded that of the TNF-α immunoreactivity. Both the NMDA-R1 and TNF-α immunoreactivities were decreased with time. To investigate the effect of glutamate on TNF-α expression, cultured rat RPE cells were treated with 1 mM glutamate, and TNF-α gene expression was examined by RT-PCR. TNF-α mRNA expression was increased after the 4-day glutamate treatment. These results suggest that TNF-α is synthesized in RPE cells, and may play an important role in the development of retinal degeneration induced by ischemia/reperfusion insult at an early stage. Glutamate may induce TNF-α expression via NMDA-R 1.