To investigate whether vaccination could induce lethal shock and which mechanisms are involved in this phenomenon, we tested a panel of autoantigens or diabetes-irrelevant peptides or proteins in nonobese diabetic (NOD), Balb/c, and C57Bl/6 mice. Of the antigens tested, only nondiabetogenic hen egg white lysozyme induced a severe form of shock exclusively in NOD mice. The mechanism involved is suggestive of a Th(2)-mediated anaphylactic reaction possibly connected to activation of PAF and triggering of DIC.