TALL-1/BAFF/BLyS was recently identified as a member of the tumor necrosis factor (TNF) ligand family. The crystal structure of the functional soluble TALL-1 (sTALL-1) has been determined at 3.0 A. sTALL-1 forms a virus-like assembly with 200 A diameter in the crystals, containing 60 sTALL-1 monomers. The cluster formation is mediated by a "flap" region of the sTALL-1 monomer. The virus-like assembly was also detected in solution using gel filtration and electron microscopy. Deletion of the flap region disrupted the formation of the virus-like assembly. The mutant sTALL-1 still bound its receptor but could not activate NF-kappaB and did not stimulate B lymphocyte proliferation. Finally, we found the virus-like cluster of sTALL-1 exists in physiological condition. We propose that this virus-like assembly of sTALL-1 is the functional unit for TALL-1 in vivo.