We performed side-by-side experiments to compare the behavior of four strains of Escherichia coli and one strain of Pseudomonas aeruginosa in fresh human and mouse blood. Bacteria were multiplied in mouse whole blood and plasma but were killed in human whole blood and plasma. The percentage of granulocytes associated with fluorescence-labeled heat-killed E coli relative to total leukocytes counted was higher in human compared to mouse blood as assessed by flow cytometry analysis. Concentrations of proinflammatory cytokines were high in human blood, but undetectable in mouse blood despite high concentrations of bacteria. We conclude that bacterial killing, phagocytosis, and cytokine induction in blood during human bacteremia with these organisms are probably not mimicked in mouse models of bacterial challenge. Understanding the mechanisms for low cytokine induction with high bacterial loads in mouse blood may be helpful to interpret murine models of bacteremia and develop new approaches for treating sepsis in humans.