The plasma membrane (oolemma) of the hamster egg retains the ability to fuse with spermatozoa even after exhaustive treatment with proteases and glycosidases. In contrast, when mouse oolemma is treated with proteases, the ability of eggs to fuse with spermatozoa is reduced. In the present study, similar treatments effective in reducing fusibility in the mouse were reexamined in the hamster. Of the several enzymes and treatments tested, only trypsin in Ca2+-free medium significantly reduced the hamster oolemma's ability to fuse with spermatozoa. This is suggestive of a cadherin-like system of binding and fusion. When hamster oolemmae were treated with the same protease regimen that reduced fusibility of mouse oolemma for mouse spermatozoa, heterologous fusion of hamster oolemmae with mouse spermatozoa was reduced, without affecting the fusion of these oolemmae with hamster spermatozoa. These data suggest that a protease-sensitive oolemma molecule is of critical importance for mouse sperm-oolemma fusion but not for hamster sperm-oolemma fusion.