Mononuclear leukocytes (MNLs) have been used as a model of β-adrenergic responsiveness of airway smooth muscle, but the relevance of this model remains controversial. The basenji greyhound (BG) dog model of airway hyperresponsiveness shares some features with human asthma, and airway smooth muscle shows a selective impairment in isoproterenol-stimulated adenylyl cyclase activity. In this study, MNL membranes were obtained from these same dogs, and the β-adrenergic receptor–adenylyl cyclase cascade function was compared with that in airway smooth muscle. β-Adrenergic receptor numbers and affinities for iodine 125–cyanopindolol were similar in the two dog groups (receptor numbers [B_max] = 441 ± 101 and 447 ± 61 fmol/mg protein and dissociation constant [K_d] = 269 ± 44 and 312 ± 60 pmol/L for mongrel and BG MNLs, respectively). Quantities of the G_s⍺ protein were not different in the membranes as determined by immunoblotting. Stimulation of adenylyl cyclase by isoproterenol (100 μmol/L) was impaired in MNL membranes of BG membranes (22% ± 4% increase over guanosine triphosphate [10 μmol/L]) compared with mongrel membranes (47% ± 8.6% increase over guanosine triphosphate [10 μmol/L], p < 0.05). Stimulation of adenylyl cyclase by prostaglandin E₁ (10 μmol/L), NaF (10 mmol/L), or forskolin (10 μmol/L) did not differ in membranes from the two groups. No difference was found in the lymphocyte subsets in the two groups as determined by flow cytometry. These findings are qualitatively similar to studies of trachealis muscle membranes from these same dogs. We have found a selective impairment of isoproterenol stimulation of adenylyl cyclase in membranes prepared from MNLs of the BG dog, which was previously found in airway smooth muscle membranes despite no decrease in numbers of β-adrenergic receptors. (J A LLERGY CLIN I MMUNOL 1995;95:860-7.)