The unintended pregnancy rate worldwide is approximately 48% of all pregnancies. This high unintended pregnancy has caused burdens not only to the mother and the child but also the overall socioeconomic infrastructure. One of the causes of unintended pregnancy is the high failure rates (13-29%) of over-the-counter methods. As such, the novel contraceptives that are easily assessable and effective methods, such as non-hormonal contraceptives, could mitigate this unintended pregnancy issue. Our laboratory showed that inhibition of semen liquefaction in the female reproductive tract significantly prevented sperm migration in mice. Semen liquefaction is a biochemical process governed by prostate-specific antigen (PSA; a serine protease enzyme). PSA cleaves gel-forming proteins (semenogelins; SEMGs) and changes the semen from gel-like to watery viscosity. Highly viscous semen and abnormal liquefaction reduce sperm motility and contribute to infertility. However, specific inhibition of PSA activity has not been evaluated as potential contraceptive method for blocking semen liquefaction. To determine whether specific inhibition of PSA activity can be developed as a novel contraceptive target, fresh ejaculates were treated with PSA antibody for 30 min for viscosity assay and 4 hours for sperm motility assay. We found that PSA antibody 1) effectively inhibited liquefaction by preventing degradation of SEMGs resulting in a higher semen viscosity compared to control and 2) significantly decreased sperm motility. Moreover, we found that there are small molecule PSA-specific inhibitors that could act similarly to prevent semen liquefaction in humans. In conclusion, inhibition of PSA activity using a neutralizing antibody can be developed for potential usage as novel, non-hormonal contraceptives for both men and women.