Papavarine, cholera toxin, and isoproterenol each elevated cyclic AMP in cultured rat retinal pigment epithelium and reduced the phagocytosis of isolated rod outer segments (38–66% of controls) during a 4 hour incubation. In addition, cultured pigment epithelium was preincubated with 25 mM exogenous cyclic AMP for two days and then incubated with outer segments for 4 hours either in the continued presence of exogenous cyclic AMP (condition A) or in the absence of exogenous cyclic AMP (condition B). Under condition B phagocytosis was 38% higher than under condition A. Intracellular cyclic AMP decreased under condition B but remained constant under condition A. These observations provide evidence that short term decreases in intracellular cyclic AMP are associated with increases in phagocytosis of outer segments by cultured rat pigment epithelium.