Autoimmune premature ovarian failure causes young women to develop menopausal symptoms and infertility. A similar syndrome appears in mice with postthymectomy autoimmune premature ovarian failure. We demonstrate that these mice develop antibodies against a 125-kDa protein located in the oocyte cytoplasm (ooplasm). By screening a mouse ovarian complementary DNA expression library with autoimmune serum, we have identified a novel mouse gene with a 3.75-kb ovarian transcript, the expression of which is restricted to the oocyte. The longest open reading frame (3333 bp) encodes an oocyte-specific protein, designated OP1 (ooplasm-specific protein 1). The protein is composed of 1111 amino acids with a predicted molecular mass of 125,502 Da. Based on its primary structure, it appears to be novel and has no motifs to suggest a localization other than in the cytoplasm. The ability of immune serum from mice with ovarian autoimmunity to react specifically with recombinant OP1 raises the possibility that OP1 as an antigen may play a role in murine autoimmune premature ovarian failure.