Previous studies have demonstrated elevated cyclic 3',5'-adenosine monophosphate specific phosphodiesterase (PDE) activity in mononuclear leukocytes (MNL) from patients with atopic dermatitis (AD) and with allergic respiratory disease. We have studied the effect of PDE inhibitors on MNL from normal subjects and from patients with AD. We measured PDE activity in MNL after in vitro exposure to Ro20-1724, theophylline, and isobutylmethylxanthine. The effect of PDE inhibitors was also measured in MNL of patients during and after oral theophylline therapy. There was a dose-response effect of Ro20-1724 on PDE activity of AD cells. This activity was significantly more inhibited than that in MNL of normal subjects or in MNL of theophylline-treated patients with AD. The inhibition pattern of PDE in MNL of treated patients with AD did not vary significantly from the pattern observed in MNL from normal patients. Two weeks after oral theophylline was stopped, the PDE activity in MNL was once again susceptible to in vitro inhibition. The relative resistance of MNL to PDE activity in normal subjects to in vitro PDE inhibitors may be due to the existence of different PDE enzyme forms or the presence of endogenous inhibitors. The clinical importance of the tachyphylaxis observed is uncertain, but our results suggest that intermittent dosing with PDE inhibitors may provide a therapeutic advantage in treatment of AD and other atopic diseases.