Experiments were designed to test for possible differing modulatory effects of either intravascular or extravascular prostaglandins (PGs) on local edema induced by intradermally injected inflammatory mediators in the rabbit. Local extravascular PGI2, PGE2 and 15-methyl-PGE1, with similar potencies, had a marked potentiating effect on local edema induced by C5a des Arg. Local extravascular PGI2 also potentiated edema when tested with leukotriene B4 (LTB4), bradykinin, and histamine. However, intravenously infused PGI2 at 50 ng/kg/min reversed the enhancing effect of local extravascular PGI2. At this dose the attenuating effect of PGI2 was selective for the polymorphonuclear (PMN) leukocyte-dependent edema induced by C5a des Arg and LTB4, but had no effect on edema induced by the nonchemoattractants histamine and bradykinin. Similarly, edema induced by N-formyl-methionyl-leucyl-phenylalanine was suppressed, but not that induced by platelet activating factor. 15-Methyl-PGE1, at 300 ng/kg administered systemically (subcutaneously), also selectively suppressed PMN-dependent edema. However, at higher doses of 3 and 60 micrograms/kg attenuation was nonselective and associated with a fall in systemic arterial blood pressure. These experiments demonstrate that the site of PG generation and action is an important determinant of its influence on edema formation.