Cultured normal rat retinal pigment epithelium (PE) ingested six times more rod outer segments in the presence of 20% fetal bovine serum than in serum-free medium. PE cultured from Royal College of Surgeons (RCS) rats with hereditary retinal dystrophy, known to have a defect in vivo in the phagocytosis of shed outer segment tips, ingested amounts of outer segments comparable to normal PE in serum-free medium but did not show an increase in the presence of serum. In both strains of rat PE phagocytosis of latex spheres was similar in the absence of serum and was six-fold higher in the presence of serum, showing that the RCS phagocytic deficiency for outer segments in vitro is not due to a general defect in the phagocytic capacity of the cell. Increased phagocytosis of outer segments by normal PE was observed in the presence of the high molecular weight fraction of ultrafiltered serum but was not seen with serum that was heated at 93 degrees C or precipitated with 5% trichloroacetic acid. Bovine serum albumin had no effect on phagocytosis. These results are consistent with the idea that the phagocytosis of outer segments by cultured normal rat PE, but not by cultured RCS rat PE, is increased in the presence of a specific protein or other macromolecular component of fetal bovine serum.