The gp130 receptor is activated by interleukin-6 (IL-6) cytokines in response to inflammation, pressure overload, and ischemic injury and signals via JAK-STAT, SHP2-Ras-ERK and PI3/Akt pathways. In the heart, gp130 signaling has been implicated in cardiomyocyte hypertrophy and survival, ECM remodeling, and inflammation. Here we determined the role of individual downstream signaling pathways activated from the gp130 receptor in the mouse heart after myocardial infarction (MI). Using the Cre-LoxP system, we generated mice harboring cardiomyocyte-restricted mutations in the gp130 receptor, e.g. a complete knock out of gp130 (CKO), a mutation in the gp130 receptor abrogating gp130 SHP2-Ras-ERK signaling (CKO-ERK) and a mutation in the gp130 receptor abrogating JAK-STAT signaling (CKO-STAT). All genotypes are viable and born with the expected Mendelian ratio. No specific cardiac phenotype was observed under the baseline condition. Intravenous injection with the IL-6 cytokine, leukemia inhibitory factor (LIF), induced a rapid activation of ERK and STAT3 in left ventricles (LVs) from WT mice while in CKO, LV activation of ERK and STAT3 was absent. In CKO-ERK LVs, LIF induced a normal activation of STAT3, but ERK1/2 activation was absent. In contrast, in CKO-STAT LVs, LIF-induced activation of STAT3 was absent and ERK1/2 was hyperactivated. No specific activation of Akt was observed upon LIF injection. Within the first 14 days post MI, mortality rate was higher, MI size was larger and cardiac function more deteriorated in all gp130 mutations compared with wildtype (WT) siblings. Long-term post MI mortality was highest in CKO-ERK (76%, P<0.01 vs WT) followed by CKO (61%, P<0.01 vs WT). No increased long-term MI mortality was observed in CKO-STAT compared with WT mice. CKO-ERK mice displayed attenuated cardiomyocyte hypertrophy and increased collagen degradation in the infarct border zone compared with WT mice. CKO-STAT mice showed elongation of cardiomyocytes and enhanced fibrosis compared with WT. CKO mice displayed elongation of cardiomyocytes and decreased capillary density compared with WT. For the first time we have dissected gp130-mediated signaling pathways according to their specific role on cardiac remodeling after MI. In this regard, we could show that gp130 mediated ERK1/2 activation controls cardiomyocyte hypertrophy and limits collagen degradation in the MI border zone, while gp130 mediated STAT activation protects from cardiomyocyte elongation and extensive fibrosis.