Peptide fragments, derived from prostatic acidic phosphatase, are secreted in large amounts into human semen and form amyloid fibrils. These fibrillar structures, termed semen-derived enhancer of virus infection (SEVI), capture HIV virions and direct them to target cells. Thus, SEVI appears to be an important infectivity factor of HIV during sexual transmission. Here, we are able to demonstrate that epigallocatechin-3-gallate (EGCG), the major active constituent of green tea, targets SEVI for degradation. Furthermore, it is shown that EGCG inhibits SEVI activity and abrogates semen-mediated enhancement of HIV-1 infection in the absence of cellular toxicity. Therefore, EGCG appears to be a promising supplement to antiretroviral microbicides to reduce sexual transmission of HIV-1.