A clinical association between insulin therapy and hypophosphatemia has frequently been made but a dose-response relationship has not been reported. Furthermore, the rapidity by which hypophosphatemia may be induced following an increment in plasma-free insulin concentration is not well defined. Therefore this study compared the effects of different rates of insulin infusion on the changes in plasma phosphate concentration in ketotic, hyperglycemic diabetic man. Sixteen prospective studies were performed in four insulin-dependent ketotic diabetic subjects. Insulin was infused according to one of four different protocols: high dose (1.0 U/kg/hr), low dose (0.1 U/kg/hr), very low dose (0.01 U/kg/hr) and control (saline only). Plasma phosphate, glucose, and free insulin concentrations were measured sequentially during the 60 min infusion periods. We observed that plasma phosphate concentrations declined significantly only with low-dose and high-dose insulin infusions. The magnitude and rapidity of fall of the mean phosphate concentration were greatest with high-dose insulin infusion. Significant hypophosphatemia can be observed within 30 min following the onset of insulin therapy.