In HIV-infected women, co-infections that target the placenta, fetal membranes, genital tract, and breast tissue, as well as systemic maternal and infant infections, have been shown to increase the risk for mother-to-child transmission of HIV (MTCT). Active co-infection stimulates the release of cytokines and inflammatory agents that enhance HIV replication locally or systemically and increase tissue permeability, which weakens natural defenses to MTCT. Many maternal or infant co-infections can affect MTCT of HIV, and particular ones, such as genital tract infection with herpes simplex virus, or systemic infections such as hepatitis B, can have substantial epidemiologic impact on MTCT. Screening and treatment for co-infections that can make infants susceptible to MTCT in utero, peripartum, or postpartum can help reduce the incidence of HIV infection among infants and improve the health of mothers and infants worldwide.