When human retinas are cultured in the presence of various phosphodiesterase (PDE) inhibitors or cyclic nucleotide analogues, rod photoreceptors undergo degenerative changes followed by cell death within 8 hours of incubation, whereas cone photoreceptors and other retinal cells are affected minimally. In the present study we found that the PDE inhibitor, isobutylmethylxanthine (IBMX), as well as the dibutyryl analogues of cGMP and cAMP, inhibited protein synthesis in short-term cultures of human retinas under conditions where uptake of exogenously supplied 3H-leucine was not diminished (relative to controls). The results of an autoradiographic analysis suggested that inhibition of protein synthesis by these drugs occurred to a greater extent in rod photoreceptors than in cones or other retinal cells, and that this phenomenon happened prior to the onset of any morphological changes. When retinas incubated in IBMX for 4 hours were returned to control medium for an additional incubation, rods recovered their ability to synthesize proteins and cell viability was maintained. The results of polyacrylamide gel electrophoresis indicated that IBMX caused a general inhibition of retinal protein synthesis rather than affecting the synthesis of specific retinal proteins. These observations are discussed with regard to possible mechanisms underlying rod-specific photoreceptor degeneration.