HIV-1 infection is known to lead to a massive depletion of CD4(+) T cells, and the Fas/FasL and TRAIL/TRAIL-receptor systems have been reported to be one of the mechanisms of CD4(+) T cell apoptosis in HIV-1 infection. RCAS1 (a receptor-binding cancer antigen expressed on SiSo cells) is also an apoptosis-associated protein that induces apoptosis in receptor positive-cells including T cells, and NK cells. To investigate the role of RCAS1 in HIV-1 infection, we stimulated CD4(+) T cells, monocytes, and several cell lines by HIV-Tat protein and thus showed that Tat significantly increased the mRNA transcription levels and the secretion of soluble RCAS1 in CD4(+) T cells and monocytes. We also showed that the apoptosis induced by HIV-Tat was blocked by inhibiting the expression of RCAS1, using small interfering RNA (siRNA), which was specific for RCAS1. These results indicate that RCAS1 is one of the mechanisms of CD4(+) T cell depletion induced by HIV infection.