The immunosuppression seen following major trauma and burns has long been attributed in part to prostaglandin E (PGE). This has been due primarily to the demonstration that PGE levels are elevated following burns and that when PGE is added to leukocyte cultures, it impairs multiple types of leukocyte functions. We investigated the effect of a new long-acting PGE derivative, 16,16-dimethyl-PGE, on immune function in multiple animal models. The PGE derivative had no effect on mortality in burn sepsis models but improved mean survival times in an Escherichia coli peritonitis model. The PGE derivative impaired neutrophil migration into burn wounds at lower dosages. In a rat burn model, when PGE was administered parenterally, it failed to impair cell-mediated immunity at any dosage and improved lymphocyte function at certain dosages. These data indicate that PGE may not be as immunosuppressive in in vivo models as it has been shown to be in in vitro models.