The phosphodiesterase from the visual cells of rd mice and affected Irish setter dogs has been analyzed, using biochemical, biophysical, and immunological techniques. The authors' findings demonstrate that the mechanisms that cause a deficiency in phosphodiesterase activity in rd mice and Irish setter dogs are distinctly different. Apparently, the phosphodiesterase complex is normal in affected Irish setter dogs but is abnormal in rd mice. The criteria used for determining the normalcy of the phosphodiesterase complex were sedimentation characteristics, immuno-cross-reactivity, and histone-activation, which is shown to be a unique characteristic of the visual cell enzyme. According to these criteria, the phosphodiesterase complex in the visual cells of rd mice is either absent or abnormal from the onset of visual cell differentiation until degeneration, because it exhibits no cross-reactivity with antibody to phosphodiesterase; it is not activated by histone; and if present, it exhibits abnormal sedimentation characteristics and perhaps subunit structure. On the other hand, phosphodiesterase from the visual cells of affected Irish setter dogs is normal by the same criteria, because it cross-reacts with antibody against phosphodiesterase; it is activated by histone; and it exhibits normal sedimentation and electrophoretic patterns. It is proposed that depressed levels of phosphodiesterase activity in affected setter photoreceptors are due, perhaps, to a defect in the light-initiated cascade which activates the enzyme normally, in situ.