Atrial natriuretic peptide (ANP) via its receptor guanylyl cyclase-A (GC-A) moderates cardiomyocyte (CM) growth possibly by preventing excessive activation of Na+/H+ exchanger NHE-1 and subsequent increases in cardiomyocyte pHi and Ca2+i. The downstream pH and/or Ca2+-dependent effector(s) leading to hypertrophy in GC-A -deficient (GC-A -/-) mice are unclear. In the present study we investigated the role of CaMKII. Inhibition of CaMKII with KN-93 (10 mM) significantly attenuated increased Ca2+i transients in GC-A -/- CM and had no effect on wildtyp (WT) cells. Chronic treatment of GC-A -/- mice with KN-93 (1 mmol/kg/d, i.p., 5 weeks) did not affect the hypertensive phenotype but significantly reversed ventricular hypertrophy and fibrosis. Increased expression and autophosphorylation of CaMKII in GC-A -/- hearts regressed on WT level after treatment with KN-93. These findings suggest that CaMKII has a critical role both in altered cardiomyocyte Ca2+i handling and cardiac remodelling of GC-A -/- mice.