Passive transfer of monoclonal anti-progesterone antibodies shortly after mating blocks the onset of pregnancy in different species (mouse, rat, and ferret). Here we report that BALB/c mice can be actively immunized against progesterone, and hence against pregnancy, by means of rabbit anti-idiotypic antibodies specific for a mouse monoclonal antiprogesterone antibody, DB3. Some of the anti-idiotypic antibodies reacted with the steroid-combining site on the DB3 molecule. In response to repeated anti-idiotypic immunization, mice produced serum anti-progesterone antibodies (up to 100 ,ug/ml) that resembled DB3 in idiotypy, affinity, and specificity for progesterone and other steroid ligands. Thus an anti-idiotype can mimic the antigenicity of a steroid hormone with a high degree of accuracy. Compared with immunization with a progesterone-bovine serum albumin conjugate, the anti-progesterone response to anti-idiotype was considerably lower and clonally restricted. When mated after completion of the immunization course, the fertility rate of anti-idiotypeimmunized mice was reduced to 30% from a control level of 91%. The anti-fertility effect was correlated with the circulating anti-progesterone concentration in individual animals and persisted for 4 or 5 estrous cycles. Active immunization with progesterone-bovine serum albumin was a highly effective means of rendering mice infertile; it reduced the fertility rate to zero over 16 or 17 estrous cycles. Our results suggest that anti-idiotypes may form the basis of contraceptive vaccines.Immunological intervention in pregnancy is of interest as a possible approach to contraception and the control of reproduction. The targets for such intervention include the hormones associated with pregnancy and antigens on gametes. Thus, recent work has focused on a vaccine against human chorionic gonadotrophin (1) and immunization against sperm-specific proteins (2). Progesterone, the key steroid hormone required for the establishment and maintenance of pregnancy, is another possible target molecule. Active antiprogesterone immunization with a progesterone-protein complex blocks pregnancy in rats (3) and rabbits (4), and we have shown that passive immunization with anti-progesterone monoclonal antibodies (mAbs) shortly after mating prevents implantation and pregnancy in mice (5, 6), rats (7), and ferrets (8). The action of anti-progesterone antibody involves sequestration of the hormone in the circulation, preventing it from reaching progesterone receptors in uterine tissue (9); in addition, we have recently shown that antibody becomes localized specifically on the surface of progesterone-sensitive areas of the uterus (luminal and glandular epithelium) just before the time of implantation, indicating the possibility of a local blocking action affecting hormone uptake (10).Anti-idiotypes (Id) are antibodies that recognize the antigen-combining regions of other antibodies and as such have been widely used as antigen mimics and experimental vaccines (11,12). A possible route to ...