Annexin II receptor (AXIIR) is also known as chromosome 5 open reading frame 39 (C5orf39), it was originally identified as a cell surface receptor for Annexin II. AXIIR gene is peculiar to human. So far, the only known function about AXIIR is mediating Annexin II signal. In this study, we find that over-expression of AXIIR induces apoptosis, and this phenomenon is found in multiple human cell types. AXIIR is located in cytoplasm, binds to and activates pro-Caspase-8, which subsequently activates Caspase-3/7. AXIIR also down-regulates BCL2, BCL-XL, and activates Caspase-9, which finally activates Caspase-3/7 as well. Over-expression of BCL-XL does not affect AXIIR-induced apoptosis, whereas inhibition of Caspase-8 partially abolished AXIIR-induced apoptosis. AXIIR induces apoptosis independent of Annexin II and FADD. AXIIR is neither required for TRAIL-induced Caspase-8 activation. Although the transcriptional level of AXIIR in multiple cell types is considerably high, the translational level of AXIIR can hardly be detected. And inhibition of protein degradation pathways does not elevate AXIIR expression. Taken together, our observations reveal that besides being a cell surface receptor of Annexin II, AXIIR can also be located in cytoplasm and act as a novel inducer of apoptosis in human cells, partially through activating Caspase-8 in a manner that is different from conventional apoptotic pathways. The translation of AXIIR is generally tightly inhibited in cells. The physiological significance of such inhibition might be to prevent cells from apoptosis.