Semen deposition results in modulated immunity and an inflammatory response of the genital mucosa, which promotes conditions facilitating conception and pregnancy. These semen-induced alterations in the female reproductive tract can also have implications for the sexual transmission of viral infections such as HIV-1. Semen is not only a vector for HIV-1 but also a carrier for pro- and antiviral factors. Semen induces significant mucosal changes upregulating gene, and transcription factors leading to recruitment and activation of HIV target cells, stimulation of HIV replication and potentiation of Toll-like receptor responses. Although more research is needed to clearly elucidate the resulting collective effects of all these factors, semen modulation of the cervicovaginal microenvironment and immune system appears to lead, through multiple mechanisms, to mucosal changes facilitating viral entry and replication, likely resulting in enhanced susceptibility to acquire HIV-1 infection.