We have previously reported that the complement inhibitor SP-40,40 is present in human seminal plasma. We also speculated that other inhibitors of the vascular complement system may be present within semen for the purpose of providing protection for sperm against complement within the male and/or female genital tract. In this study, we examined human seminal plasma and spermatozoa for the presence of several major complement regulatory proteins. We detected the presence of decay-accelerating factor (DAF) and CD59 and have confirmed the presence of Membrane Cofactor Protein (MCP) and SP-40,40 on human sperm. As an approach to the possible functional significance of these inhibitors on sperm membranes, the presence of two key complement components, C3 and C9, in seminal plasma was used as a criterion for an active complement system. We failed to detect C9 in seminal plasma and showed that its concentration was less than 5% of the level detected in blood plasma. C3 was also undetectable in seminal plasma; as assessed by Western transfer, its level was less than 0.3% of that in blood plasma. The low level or indeed the absence of key components of the complement system in seminal plasma-together with the finding that human sperm possess an extensive array of the vascular complement inhibitors, some of known physiologic significance-strongly suggests that their role on sperm is to protect sperm from complement lysis in the female rather than the male genital tract.