The effects of Ca²⁺ and calcitonin infusions on circulating glucagon, glucose, C-peptide, Ca²⁺, and calcitonin were investigated in hyperglucagonaemic insulin-dependent diabetics. In 14 insulin-deprived diabetics and 12 healthy volunteers 2 h infusions of saline (0.154 mol/l), Ca²⁺ (0.375 mmol/kg body weight), and calcitonin (4.5 IU/kg body weight) were performed. There were no significant changes during saline infusion. In the diabetics, Ca²⁺ infusions induced a rise of plasma Ca²⁺ up to 3.2±0.1 mmol/l and a fall of circulating glucagon (-26.4±5.7%; p<0.001) and glucose (-23.3 ±3.6%; p<0.05). Plasma calcitonin rose to twice basal values (p<0.025). During calcitonin infusions plasma Ca²⁺ decreased slightly to 2.1±0.2 mmol/l; a fall was found in both glucose (— 24.4±4.0%; p<0.05) and circulating glucagon (-22.5±4.3%; p<0.001). Two groups of 6 healthy volunteers were subjected to saline and Ca²⁺, or to Ca²⁺ and calcitonin infusions. Both Ca²⁺ and calcitonin infusions induced a fall of serum insulin (— 30.1±6.6%; p< 0.05). Calcitonin depressed circulating glucagon by-18.6±4.4% (p<0.025), whereas during Ca²⁺ infusions glucagon decreased only by -6.5±1.9% (p>0.1). We conclude from our results that an increase of circulating calcitonin induced by Ca²⁺ infusions or by exogenous calcitonin administration appears to depress elevated circulating glucagon and glucose in insulin-dependent diabetics.