We determined that YopE and YopH block Rac2 activation and calcium flux, respectively, to inhibit neutrophil primary granule release in isolated human neutrophils.These results demonstrate that <i>Y. pestis</i> coordinates the inhibition of neutrophil primary granule release through the activities of two distinct effectors, and this inhibition promotes <i>Y. pestis</i> survival during primary pneumonic plague.<b>IMPORTANCE</b><i>Yersinia pestis</i> is the causative agent of plague and is one of the deadliest human pathogens.The pneumonic form of <i>Y. pestis</i> infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of <i>Yersinia pestis</i> pulmonary infections are incompletely understood.