YopM of Yersinia pestis has previously been shown to be necessary for full virulence in mice and to be able to bind human alpha-thrombin. This activity prompted the hypothesis that YopM, functioning extracellularly during plague, might be accessible to neutralization by antibody and hence might be a protective antigen. This study tested this hypothesis and found that YopM was not protective, either by passive or active immunization, in inbred or outbred mice. These findings showed that either YopM-specific antibody does not have access to YopM during experimental plague or the function of extracellular YopM is not neutralizable by antibody. Exogenously supplied YopM partially restored virulence to a YopM- strain of Y. pestis while having no effect on lethality of Listeria monocytogenes. These findings indicate that YopM does not significantly alter host defenses important for resistance against heterologous infection (Listeria monocytogenes) but raise the possibility that YopM has a minor extracellular function specific to homologous infection (Y. pestis).