Alkaline phosphatase (AP) is a phosphate transferase present in bacteria and eukaryotes. In previous studies, we have shown that AP is able to dephosphorylate lipopolysaccharide (LPS) at physiological pH levels. Because LPS is the causative agent of gram-negative sepsis, we hypothesize that AP might be used as a medication during early stages of LPS-induced septic shock. We have demonstrated protective effects of AP when this enzyme was administered simultaneously with LPS. However, a major question of anti-LPS therapies is whether they are also effective after systemic infiltration of whole bacteria and if they also act in later stages of the disease. To test this, we explored the protective effects of AP from human placenta (plAP) in a bacterial challenge model in Balb/c mice. AP was intravenously administered 20 min after a bacterial intraperitoneal inoculation of 2 to 5 x 10 CFU of Escherichia coli suspended in a 100-microL volume of saline. It was shown that AP attenuated the systemic host response upon E. coli. Body temperature was normalized as compared with untreated septic mice. Also, serum nitric oxide levels 24 h after the injection of bacteria were reduced almost to control levels in mice that received AP. Moreover, survival after 24 h was significantly higher in the AP-treated group compared with the nontreated control group.