A novel Death Effector Domain-containing protein, DEDD2, is closest in amino acid sequence homology to Death Effector Domain-containing DNA-binding protein, DEDD. DEDD2 is expressed widely in adult human tissues with highest levels in liver, kidney and peripheral blood leukocytes. DEDD2 interacts with FLIP, but not with FADD or Caspase 8. Over-expression of DEDD2 induces moderate apoptosis and results in substantial sensitization to apoptosis induced by Fas(CD95/APO-1), TRAIL(Apo2L), or FADD. These findings suggest that DEDD2 is involved in the regulation of nuclear events mediated by the extrinsic apoptosis pathway.