Rat erythrocytes fuse when treated with the membrane mobility agent, 2‐(2‐methoxyethoxy)ethyl‐cis‐8‐(2‐octylcyclopropyl) octanoate (A2C) and Ca2+, whereas human cells do not. Membrane proteolysis promoted by calpain is required for rat cell fusion [(1986) Eur. J. Biochem., in press]. Human calpain induced a selective proteolysis in both the human and rat erythrocyte ghosts (mainly band 4.1 in the human, band 4.1 and band 3 in the rat cell) and rendered them fusible. Calpastatin (calpain inhibitor) prevented A2C‐induced fusion in both ghosts, via inhibition of proteolysis. The human erythrocyte has excess calpastatin and resists A2C‐promoted fusion. A regulatory role of calpastatin in membrane fusion is thus indicated.