Recently, we reported that leukemia inhibitory factor (LIF), a member of the interleukin (IL)-6 cytokine family, transduced hypertrophic and cytoprotective signals via Januas Kinase-signal transducer and activator of transcription (JAK-STAT) pathway in cardiac myocytes. Angiotensin II (AII) is also known to activate STATs and reported to induced apoptosis in adult rat ventricular myocytes. In the present study, we investigated potential interactions between gp130 dependent and AII signaling pathways, by examining AII regulation of LIF-induced anti-apoptotic effect and STAT3 activation in cardiac myocytes. Although LIF attenuated the DNA fragmentation induced by serum depletion, AII augmented the DNA fragmentation in cultured neonatal rat cardiac myocytes. Furthermore, LIF-mediated cytoprotective effect was inhibited by AII pretreatment. LIF rapidly and transiently tyrosine phosphorylated STAT3 in cardiac myocytes which was not observed by AII. AII pretreatment inhibited LIF-induced phosphorylation of STAT3 in a dose dependent manner. This inhibitory effect of AII on STAT3 activation was blocked by the AII type I (AT1) receptor antagonist CV11974. These results demonstrate that negative crosstalk between gp130 and AT1 receptor dependent signaling exists in cardiac myocytes. This crosstalk may contribute to the modulation of pathophysiological process in myocardial disease.