We have shown that genistein inhibits the growth of adult T-cell leukemia (ATL) cells in vitro and in vivo, and this leads to pronounced G2/M arrest. This report shows that genistein induces apoptotic death in ATL cells. Although the pan-caspase inhibitor, Z-VAD-fmk, did not inhibit genistein-induced apoptosis, release of apoptosis-inducing factor (AIF) into the cytosol occurred. Poly-ADP ribose polymerase inhibition also abrogated genistein-induced apoptosis. Genistein decreased nuclear p65 translocation and IκBα phosphorylation, and downregulated the anti-apoptotic proteins, XIAP, cIAP and survivin, NF-κB-responsive gene products. Thus, genistein is a promising agent for ATL that induces caspase-independent apoptosis through inhibition of the NF-κB pathway.