The primary physiological role of complement proteins lies in augmenting host defense to microorganisms. Among several cascade products, complement components C3 and C5 are cleaved and activated through proteolytic processing during immune activation following exposure to HIV-1. This reaction generates the small peptide anaphylatoxins C3a and C5a, which bind to G-protein coupled membrane receptors that sensitize the response of human T-lymphocytic cells to multiple cytokines including CXCL12/SDF-1. CXCL12 is an alpha chemokine that binds to the CXCR4 membrane receptor, which also functions as a co-receptor for X4-tropic HIV-1. Given the importance of complement activation in immune function and the bioactive nature of complement cleavage products we investigated here the role of C3a in HIV-1 infection of human thymocytes. Our data illustrate a potential new link between HIV-1 infection and complement activation in which C3a anaphylatoxin may modulate infectivity by reducing the susceptibility of thymocytes to HIV-1 infection.