To learn about the pathogenesis of sepsis-associated hypocalcemia, we measured serum ionized calcium concentrations in 60 critically ill patients with bacterial sepsis; 12 (20%) had hypocalcemia. The mortality rate in the hypocalcemic patients with sepsis (50%) was higher than that in the normocalcemic patients with sepsis (29%). Only patients with gram-negative sepsis became hypocalcemic, and hypocalcemia contributed to hypotension in 7 of the 12 hypocalcemic patients. Serum calcium concentrations returned to normal in each of those patients with sepsis who survived. Hypocalcemia during sepsis occurred in previously normocalcemic patients and was multifactorial in origin, resulting from acquired parathyroid gland insufficiency, renal 1 alpha-hydroxylase insufficiency, vitamin D deficiency, and acquired calcitriol resistance. We conclude that the hypocalcemia of sepsis is associated with a high mortality rate and usually occurs in previously normocalcemic patients who acquire a defect in the parathyroid-vitamin D axis.