PURPOSE. To determine whether anterior ischemic optic neuropathy and compressi ve optic neuropathy in humans alter the photopic flash ERG and to investigate th e cellular origins of the waves that are affected by pharmacologic agents in pri mates. METHODS. Photopic flash ERGs were recorded differentially, with DTL elect rodes, between the two eyes of 22 patients with diagnosed optic neuropathy (n=17 , anterior ischemic optic neuropathy AION; n=5, compressive optic neuropathy) and 25 age-matched control subjects and in 17 eyes of 13 monkeys (Macaca mulatt a). The stimulus consisted of brief (< 5 ms) red (λmax=660 nm) Ganzfeld flashes (energy range, 0.5-2.0 log td-s) delivered on a rod-saturating blue backgrou nd of 3.7 log sc td (λmax=460 nm). An eye of the patient with ischemic changes at the disc was classified as symptomatic if it showed visual field defects with a mean deviation (MD) of P< 2%. Recordings in macaque monkeys were made before and after inner retinal blockade with tetrodotoxin (TTX) (1.2-2.1 μM; n=7), TTX+N-methyl-D-aspart ate (NMDA; 1.4-6.4 mM; n=7), and cis-2, 3 piperidine dicarboxylic acid (PDA; 3 .3-3.8 mM; n=3). RESULTS. The PhNR amplitude was significantly reduced in both symptomatic (P=3.4×10 -8) and asymptomatic (P=0.036) eyes of patients with AIO N or compressive optic neuropathy (P=0.0054) compared with control subjects. The PhNR amplitude in the symptomatic eye showed a moderate correlation with field defects (P < 0.05) similar to previous findings in open-angle glaucoma. The a- wave also was reduced significantly in the symptomatic eye (P=0.0002) of patient s with AION. The i-wave, a positive wave on the trailing edge of the b-wave pe aking around 50 ms, became more prominent in eyes in which the PhNR was signific antly reduced. In monkeys, the PhNR was eliminated by TTX. The a-wave at the pe ak and later times was reduced by TTX, further reduced by NMDA, and eliminated a fter PDA in response to the red stimuli. PDA also eliminated the i-wave. CONCLU SIONS. PhNR amplitude is significantly reduced in eyes with open-angle glaucoma , AION, and compressive optic neuropathy. Experiments in primates indicate that this reduction reflects loss of a spike-driven contribution to the photopic ERG . There also are small spike-driven contributions to the a-wave elicited by fu ll-field red stimuli. The i-wave, which becomes more prominent when the PhNR i s reduced, has origins in the off-pathway distal to the ganglion cells. PURPOSE. To determine whether anterior ischemic optic neuropathy and compressi ve optic neuropathy in humans alter the photopic flash ERG and to investigate th e cellular origins of the waves that are affected by pharmacologic agents in pri mates. METHODS. Photopic flash ERGs were recorded differentially, with DTL elect rodes, between the two eyes of 22 patients with diagnosed optic neuropathy (n = 17, anterior ischemic optic neuropathy AION; n = 5, compressive optic neuropathy) and 25 age- matched control subjects and in 17 eyes of 13 monkeys Macaca mulatt a) The stimulus consisted of brief (<5 ms) red (λmax = 660 nm) Ganzfeld flashes (energy range, 0.5-2.0 log td-s) delivered on a rod-saturating blue background nd of 3.7 log sc td (λmax = 460 nm). An eye of the patient with ischemic changes at the disc was classified as symptomatic if it showed visual field defects with a mean deviation (MD) of P <2%. Recordings in macaque monkeys were made before and after inner retinal blockade with tet (1.2-2.1 μM; n = 7), TTX + N-methyl-D-aspartate (NMDA; 1.4-6.4 mM; n = 7), and cis- 2, 3 piperidine dicarboxylic acid RESULTS: The PhNR amplitude was significantly reduced in both symptomatic (P = 3.4 × 10 -8) and asymptomatic (P = 0.036) eyes of patients with AIO N or compressive optic neuropathy The pNR amplitude in the symptomatic eye showed a moderate correlation with field defects (P <0.05) similar to previous findings in open-angle glaucoma. The a-wave also was reduced significantly in the symptomatic eye (P = 0.0002) of patient s with AION. The i-wave, a positive wave on the trailing edge of the b-wave pe aking around 50 ms, became more prominent in eyes in which the the PhNR was significantly antly reduced. In monkeys The PhNR was eliminated by TTX. The a-wave at the pe ak and later times was reduced by TTX, further reduced by NMDA, and eliminated a fter PDA in response to the red stimuli. PDA also eliminated th e i-CONCLU SIONS. PhNR amplitude is significantly reduced in eyes with open-angle glaucoma, AION, and compressive optic neuropathy. Experiments in primates indicate that this reduction reflects loss of a spike-driven contribution to the photopic ERG. There are are small spike -driven contributions to the a-wave elicited by fu ll-field red stimuli. The i-wave, which becomes more prominent when the PhNR is reduced, has origins in the off-pathway distal to the ganglion cells.