The role of the angiotensin II type 2 receptor (AT2) during alterations in cardiac size remains largely unclear. Through employment of an AT2 antagonist, the present study explored a possible involvement of the AT2 receptor during salt-induced cardiac hypertrophy in the proatrial natriuretic peptide gene-disrupted mouse (ANP-/-). ANP-/- mice received either saline solution or the AT2 antagonist, PD123319, and were then placed on a high salt diet (8.0% NaCl) for 3 weeks. Cardiac and pulmonary size, expression of the renin-angiotensin system (RAS), and the behaviour of various hypertrophy marker genes were assessed. PD123319 caused enhanced expression of the systemic RAS, yet the cardiac RAS was largely unaffected. Although AT2 blockade did not alter whole cardiac mass, right ventricle mass, as well as pulmonary mass-to-body mass ratios were significantly decreased. Collagen type I was decreased in the latter tissues, likely contributing to the regression in mass. Several players essential in the maintenance of myocardial extracellular matrix homeostasis including B-type natriuretic peptide, matrix metalloproteinase-2, tumour necrosis factor, and transforming growth factor were also significantly altered by PD123319. These data suggest that AT2 blockade is involved in significant changes in myocardial extracellular matrix components translating into decreases in tissue mass in the salt-sensitive ANP-/- animal.