We investigated the effect of extracellular Ca2+ on the uptake of immunoglobulin G (IgG)-coated normal sheep red blood cells (SRBC) by the mouse peritoneal macrophages. The uptake of SRBC was dose dependently enhanced by Ca2+ concentration. We also investigated the effect of ryanodine on the uptake of SRBC. Ryanodine showed approximately 15% inhibition of the uptake. The activity of transglutaminase (TGase) in the cytosolic fraction of macrophages was enhanced as the Ca2+ concentration increased. The uptake of SRBC decreased by the addition of histamine, a TGase inhibitor. These results suggest that TGase is involved in the receptor-mediated endocytosis system of mouse peritoneal macrophages.