Adenylate cyclase (AC) activity was studied in whole homogenates of normal and otosclerotic bone cell cultures. When Mn2+ or Ca2+ was added to the medium there was a similar increase in AC activity in both cell types. F- provoked a greater rise in normal than in pathological cells, whereas 0.01 mM guanosine triphosphate (GTP) significantly raised cAMP synthesis in otosclerotic cells only. Mn2+ + calcitonin (Ct) increased AC activity in both cell preparations. With Ca2+ as cofactor there was no significant rise in either normal or pathological cells. However, while the combination Ca2+ + Ct + GTP had little effect on normal cells, it markedly increased cAMP synthesis in the pathological cells. 1 microgram/ml of the beta-blocker propranolol inhibited the effect Ct exerts on AC in normal cells, but enhanced it in otosclerotic cells. It would, therefore, seem that the pathogenesis of otosclerosis could be associated with an alteration in the AC system associated with Ct receptors.