Photoreceptor degeneration was induced in the cone-dominant retina of the ground squirrel by intracardiac injection of iodoacetic acid. Morphology was examined and cyclic nucleotide levels were determined in retinas taken at various times between 35 min and 11 days after injection. Degenerating cone cells were first detected at day 1 and all cone cells were reduced to compact dense masses by day 4. Cellular debris was removed by macrophages that entered the photoreceptor layer from the inner neuroretina. Cyclic AMP levels of dark-adapted retinas were doubled 24 hrs after injection and were reduced to approximately 50% of the dark-adapted level of control retina between days 1 and 3. The concentration of cyclic GMP was 3 to 4 times higher than normal at 4 to 5 hrs postinjection, dropped to 9% of normal at day 4, and was 2% at day 11. Since these changes were coincident with the loss of morphologic integrity of cone cells, they imply that at least 50% of cyclic AMP and most of the cyclic GMP in the cone-dominant retina of the ground squirrel is present in cone cells. The elevation of cyclic AMP and cyclic GMP levels prior to pathological morphology suggests that the iodoacetic acid-induced disruption of cyclic nucleotide metabolism may be associated with the degeneration of the cone photoreceptors.