The protease inhibitor part of inter-α trypsin inhibitor is identical to urinary trypsin inhibitor (UTI). Preincubation of neutrophils and HUVEC cells with UTI inhibited increase of cytosolic free Ca 2 + induced by LPS. Increase of cytosolic free Ca 2 + induced by LPS in the presence of EGTA was also inhibited by UTI. In contrast, UTI did not inhibit increase of cytosolic free Ca 2 + in cells stimulated by Ca 2 + ionophore with or without EGTA. The effects of nine synthetic peptides of UTI on the concentration of cytosolic free Ca 2 + in the neutrophils induced by LPS were examined. Preincubation with a peptide of UTI domain 2, NLPIVRGPCRAFIQL (83-97), was completely inhibited by the increase of cytosolic free Ca 2 + in neutrophils. This region is identical to the trypsin inhibitor site of UTI. We propose that a function of UTI other than as a protease inhibitor is in regulation of intracellular Ca 2 + and that this is due to its trypsin inhibitor region.