CrCl3, 0.25, 0.5, 1.0, and 1.5 mmol/l inhibited glucose-induced insulin secretion in a reversible and dose dependent manner. Cr also inhibited basal secretion of insulin in the presence of 5.5 mmol/l glucose and insulin secretion stimulated by 50 mmol/l K+ or 15 mmol/l L-leucine. When 2 mmol/l theophylline was employed to potentiate the stimulatory effect of 16.5 mmol/l glucose, the inhibitory effect of 1.5 mmol/l Cr was reduced and that of 0.5 mmol/l virtually abolished. A similar reduction in the inhibitory effect of Cr was observed when the medium calcium concentration was increased from 2.5 to 5, 7.5 and 12.5 mmol/l. Cr did not alter the conversion of 14C-glucose to 14CO2 or 45Ca uptake by isolated islets. It is concluded that the inhibitory effect of Cr on insulin secretion may be mediated through interference with an intracellular function of Ca++ in the beta cell.