The effects of lithium on calcium-regulated parathyroid hormone (PTH) release were assessed in collagenase-dispersed bovine parathyroid cells. Preincubation for 4 hours with LiCl caused a dose-dependent increase in the concentration of calcium required for half-maximal inhibition of immunoreactive PTH release (the "set-point" for calcium). A significant increase in "set-point" was observed following exposure to 1.25 mM lithium, a concentration within the therapeutic range for man. This effect required preincubation with LiCl, was not seen with NaCl or KCl, and persisted despite removal of extracellular lithium. This lithium-induced abnormality in calcium-regulated PTH secretion may be a useful model system for analyzing the analogous defect in secretory control in primary hyperparathyroidism.