Hypertonic NaCl irreversibly reduced the sensitivity of the rat erythrocyte cyclic AMP phosphodiesterase to inhibition by Ro 20-1724 but not by papavarine. This effect could be prevented by 1 mM EDTA and mimicked by by CaCl2. The reduction in inhibitor sensitivity was associated with an increase in hydrolytic activity and a four-fold reduction in molecular weight as estimated by Sephadex G-200 chromatography. The response to CaCl2, like that to NaCl, was time and concentration dependent and proceeded more slowly in 2 M NaCl. This concentration of NaCl contained sufficient Ca++ as an impurity to account for its effects on inhibitor sensitivity and molecular size. However, the initial and reversible increase in inhibitor sensitivity and hydrolytic activity obtained in the presence of EDTA, probably resulted from the high salt concentration, per se.