The possibility that the deleterious renal effects of positive end-expiratory pressure (PEEP) might be avoided by prevention of its attendant cardiovascular effects with increasing intravascular volume was investigated in two groups of anesthetized swine. Group 1 (12 swine) were maintained at a normovolemic state and Group 2 (11 swine) were volume expanded with an infusion of lactated Ringer's solution. In normovolemic swine (Group 1), the addition of PEEP to controlled mechanical ventilation (CMV) caused significant decreases in cardiac output and mean aortic pressure. In addition, decreases in urinary output and osmolar, free water, and creatinine clearance occurred. Change from CMV to CMV + PEEP in Group 1 also produced increases in plasma ADH from 4.6 ± 2.4 to 10.2 ± 7 pg/ml (P< 0.01) and renin from 1.8 ± 1.0 to 4.7 ± 1.6 ng · ml-1· h−1(P< 0.01), epinephrine from 133 ± 23 to 1,060 · 636 pg/ml (P< 0.03) and norepinephrine from 46 ± 15 to 1,427 ± 839 pg/ml (P< 0.03). In hydrated swine (Group 2) addition of PEEP to CMV was not accompanied by any significant change in hemodynamic, renal, or hormonal variables. It is concluded that the short-term renal effects of PEEP are mainly due to hormonal responses that are activated by decrease in perfusion pressure. These responses can be obviated by intravascular volume expansion.