&NA;We infused recombinant human tumor necrosis factor alpha (rhTNF&agr;), lymphotoxin (rhLT), andEscherichia coli0111:B4 lipopolysaccharide (LPS) into anesthetized sheep with a lung lymph fistula to compare their effects on systemic and pulmonary hemodynamics, lung lymph dynamics, and eicosanoid release. rhTNF&agr;(25‐150 &mgr;g/kg,n=6 sheep), but not rhLT (25 &mgr;g/kg,n=3), rapidly increased lung lymph and plasma levels of 6‐keto‐prostaglandin F1&agr;(6‐k‐PGF1&agr;) and caused profound systemic vasodilation and hypotension. Meclofenamate pretreatment (10 mg/kg) of three other sheep given 25 &mgr;g/kg rhTNF&agr;prevented the increase of lymph and plasma 6‐k‐PGF1&agr;levels, systemic vasodilation, and the early (<2 hrs) but not the late (4‐6 hours) hypotension caused by rhTNF&agr;. LPS (1 &mgr;g/kg,n=11) induced a briefer increase of lymph 6‐k‐PGF1&agr;levels than did rhTNF&agr;while plasma 6‐k‐PGF1&agr;levels did not increase. LPS induced more gradual hypotension than did rhTNF&agr;but did not cause systemic vasodilation. LPS and rhTNF&agr;, but not rhLT, increased lymph thromboxane B2(TXB2) levels during the first hour of study, whereas only LPS acutely increased plasma TXB2levels. LPS caused acute pulmonary vasoconstriction and greater acute pulmonary artery hypertension than did either rhTNF&agr;or rhLT. Whereas LPS‐treated sheep required less fluid transfusion than rhTNF&agr;‐treated sheep to maintain mean systemic arterial pressure greater than 50 mm Hg, LPS infusion caused a greater increase of lung lymph protein clearance. rhTNF&agr;caused minimal alterations of lung microvascular permeability. We conclude that eicosanoid mediators contribute importantly to differences of systemic and pulmonary hemodynamics caused by these agents in sheep. rhTNF&agr;cannot account for all of the LPS‐induced hemodynamic, lung lymph, and eicosanoid responses in sheep. (Circulation Research1989;65:502‐514)