A generalized Shwartzman reaction was found to occur in non-SPF-NMRI mice given a local injection of S. marcescens lipopolysaccharide (LPS) in the footpad, followed, with an interval of 24 h, by an i.v. injection. The reaction occurred several hours after the second injection. It was characterized by disseminated subcutaneous bleedings at the mouth, anus, conjuctiva, nose tip and tail end. Most mice died within 24-48 h. The size of the LPS dose given in the footpad (5 micrograms) was found to be critical in that the reaction failed to occur with higher as well as lower doses. The reaction was found to be completely absent in mice that had received one or more systemic injections of monoclonal antibodies with neutralizing potential for murine interferon-gamma (IFN-gamma). Mice treated with control preparations, including a monoclonal antibody with binding but no neutralizing activity for murine IFN-gamma, remained sensitive to induction of the reaction. These observations assign a crucial role to endogenous IFN-gamma in the elicitation of the generalized Shwartzman reaction and open perspectives for the prevention or therapy of clinical conditions related to the Shwartzman reaction by the use of antibodies to IFN-gamma.