Studies have suggested that the significant suppression of cellular immunity following hemorrhage may be due to an increased release of prostaglandin E2 (PGE2) by macrophages. Since diets high in n-3 polyunsaturated fatty acids decrease PGE2 synthesis, we assessed whether hemorrhage-induced immunosuppression could be prevented by dietary manipulation. C3H/HeN mice were fed for 3 weeks with fat sources derived from corn oil, safflower oil, or fish oil, then bled to a mean blood pressure of 35 mm Hg maintained for 60 minutes. Following this, the animals were adequately resuscitated with fluids and killed 24 hours later. In the corn oil and safflower oil groups, hemorrhage resulted in a significant increase in PGE2 release by peritoneal macrophages, a marked suppression of peritoneal macrophage antigen presentation capacity, interleukin 1 release, splenocyte proliferation, and interleukin 2 secretion compared with shams. However, feeding mice with fish oil for 3 weeks prior to hemorrhage prevented the rise in PGE2 release and maintained normal macrophage and splenocyte functions following hemorrhage. Thus, the elevated release of PGE2 by peritoneal macrophages plays a pivotal role in hemorrhage-induced immunosuppression. Moreover, diets high in n-3 polyunsaturated fatty acids may offer a new therapeutic approach for preventing posthemorrhage immunosuppression and increased mortality from sepsis. © 1993, American Medical Association. All rights reserved.