Although the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) are important mediators of hemodynamic, metabolic, and immunologic alterations in the host during sepsis, it is not known whether there is any association between the release of these cytokines and prostanoids during sepsis. Sepsis induced by cecal ligation and puncture in rats led to a persistent elevation (p < 0.05) of plasma TNF until 10 hours, steadily increasing (p < 0.05) IL-1 plasma levels, and enhanced (p < 0.05) IL-6 plasma levels at all time points compared to the sham group. Prostaglandin E2 plasma levels were elevated (p < 0.05) at 5 hours (153 ± 29 pg/mL; control: 47 ± 11 pg/mL) and 10 hours (96 ± 16 pg/mL; control: 21 ± 5 pg/ mL). Prostaglandin E2 production by splenic macrophages (sMø) from septic animals was increased (p < 0.05) at 5 hours (9.1 ± 2.2 ng/mL) and 10 hours (5.6 ± 1.5 ng/mL) compared to controls (3.3 ± 0.3 ng/mL at 5 hours; 1.3 ± 1.3 ng/mL at 10 hours). Incubation of sMø from septic animals with ibuprofen enhanced (p < 0.05) IL-1 and TNF synthesis, while IL-6 production was reduced (p < 0.05). These results indicate that the alterations in prostanoid release and elevated plasma prostanoids may regulate the release and consequently the circulating levels of cytokines during sepsis.