Evidence suggests that the autoimmune cardiomyopathy produced by a peptide corresponding to the sequence of the second extracellular loop of the ₁-adrenergic receptor (₁-EC_II) is mediated via a biologically active anti-₁-EC_II antibody, but the mechanism linking the antibody to myocyte apoptosis and cardiac dysfunction has not been well elucidated. Since the ₁-EC_II autoantibody is a partial ₁-agonist, we speculate that the cardiomyopathy is produced by the ₁-receptor-mediated stimulation of the CaMKII-p38MAPK-ATF6 signaling pathway and endoplasmic reticulum (ER) stress, and that excess norepinephrine (NE) exaggerates the cardiomyopathy. Rabbits were randomized to receive ₁-EC_II immunization, sham immunization, NE pellet, or ₁-EC_II immunization plus NE pellet, for 6 months. Heart function was measured by echocardiography and catheterization. Myocyte apoptosis was determined by TUNEL and caspase-3 activity, while CaMKII, MAPK family (JNK, p-38, ERK), and ER stress signals (ATF6, GRP78, CHOP, caspase-12) were measured by Western blot, immunohistochemistry and kinase activity assay. ₁-EC_II immunization produced progressive LV dilation, systolic dysfunction and myocyte apoptosis. These changes were associated with activation of GRP78 and CHOP, increased cleavage of caspase 12, as well as increased CaMKII activity, increased phosphorylation of p38 MAPK, and nucleus translocation of cleaved ATF6. NE pellet produced additive effects. In addition, KN-93 and SB203580 abolished the induction of ER stress and cell apoptosis produced by the ₁-EC_II antibody in cultured neonatal cardiomyocytes. Thus, ER stress occurs in autoimmune cardiomyopathy induced by ₁-EC_II peptide, and this is enhanced by increased NE and caused by activation of the ₁-AR-coupled CaMKII, p38 MAPK, and ATF6 pathway.