This paper demonstrates that in the presence of indomethacin, a cyclooxygenase inhibitor, 100% of the mice died when infected with live Listeria, whereas none of the animals died in the absence of the drug. The death of the animals correlated with the numbers of bacteria found extraperitoneally in the spleen and not with the Ia expression of the peritoneal macrophages. Increases in the spleen bacterial numbers between mice treated with either indomethacin or a specific thromboxane synthase inhibitor, OKY1581, and those not receiving either drug, were found as early as 2-4 h after infection. The differences in the initial increased bacterial spleen counts in the presence of indomethacin were reversed by administration of a stable thromboxane A2 analog or another potent vasoconstrictor, phenylephrine. Because thromboxane A2 does not regulate macrophage or T cell functions directly, but is probably generated at the site of an infection, these data suggest an important role for the vasoconstrictive properties of thromboxane A2 in the regulation of immunity to Listeria infection.