Multiple hormone resistance in many patientswith pseudohypoparathyroidism (PHP) type la and Albright'shereditary osteodystrophy (AHO) is associated with deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) of adenylate cyclase. To study further the relationship od deficient Gs activity to hormone resistance, we evaluated endocrine function and measured Gs activity of erythrocyte membranes from AHO patients with clinical hormone resistance (PHP type la) and from family members with AHO alone (pseudopseudohypoparathyroidism). The resultsof erythrocyte membrane Gs determinations were compared to those of unaffected relatives and normal subjects. Patients with pseudopseu dohypoparathyroidism(pseudoPHP) had reductions in erythrocytemembrane Gs activity comparable to those in patients with PHP type la [43.4 ± 11.9% (±SD) for PHP type la vs. 47.8± 9.5% for pseudoPHP]. However, in contradistinction to patients with PHP type la,individuals with pseudoPHP did not have obvious endocrine dysfunction. Although deficient Gs activity appears to play an important role in the pathogenesis of these disorders,it is possible that Gs deficiency must be combined with other factors that limit cAMP production to cause clinically overt endocrine disease.