Immune infertility in humans correlates clinically with the presence of anti-sperm antibodies that trap (agglutinate) sperm in semen and cervical mucus. To test whether sperm-agglutinating antibodies can be effective contraceptive agents, several mouse anti-rabbit sperm (MARS) sperm-agglutinating monoclonal antibodies (mAbs) were developed that rapidly and completely agglutinate sperm: MARS-M3 (IgM), MARS-G16 (IgG3), and MARS-G17 (IgG3). Contraceptive efficacy of these mAbs was tested by mixing the mAb with 0.1 ml semen (approximately 1/5 of a whole ejaculate) immediately before artificially inseminating rabbits paracervically. This paracervical dose of semen provided a rigorous test since it delivered several thousand times more fertilizing doses than does a human ejaculate. All of the mAbs were contraceptively effective, and MARS-G16 reduced the number of fetuses per animal by 88% and 95% with doses of 150 microg and 2 mg, respectively. The contraceptive efficacy of the MARS mAbs in the rabbit suggests that human sperm-agglutinating mAbs may be effective agents for vaginal contraception in humans.