Activation of PKCbetaII is associated with the response to ischemia/reperfusion (I/R), though its role, either pathogenic or protective, has not been determined. In a murine model of single-lung I/R, evidence linking PKCbeta to maladaptive responses is shown in the following studies. Homozygous PKCbeta-null mice and WT mice fed the PKCbeta inhibitor ruboxistaurin subjected to I/R displayed increased survival compared with controls. In PKCbeta-null mice, phosphorylation of extracellular signal-regulated protein kinase-1 and -2 (ERK1/2), JNK, and p38 MAPK was suppressed in I/R. Expression of the immediate early gene, early growth response-1 (Egr-1), and its downstream target genes was significantly increased in WT mice in I/R, particularly in mononuclear phagocytes (MPs), whereas this expression was attenuated in PKCbeta-null mice or WT mice fed ruboxistaurin. In vitro, hypoxia/reoxygenation-mediated induction of Egr-1 in MPs was suppressed by inhibition of PKCbeta, ERK1/2, and JNK, but not by inhibition of p38 MAPK. These findings elucidate key roles for PKCbetaII activation in I/R by coordinated activation of MAPKs (ERK1/2, JNK) and Egr-1.