In patients with acute respiratory distress syndrome (ARDS), permissive hypercapnia is a strategy to decrease airway pressures to prevent ventilator-induced lung damage by lowering tidal volumes and tolerating higher arterial carbon dioxide tension. However, in experimental studies hypercapnia impairs myocardial contractility and hemodynamic function. We investigated the effect of short-term permissive hypercapnia on myocardial contractility and hemodynamics in patients with ARDS. We hypothesized that the administration of tromethamine (THAM), a buffer which does not increase carbon dioxide production, would modify these changes. In 12 patients with ARDS, permissive hypercapnia was implemented for 2 h with a target Pa(CO(2))of 80 mm Hg. Patients were randomized to have respiratory acidosis corrected by THAM (pH-corrected group), or not corrected (pH-uncorrected group). Hemodynamic responses were measured, and transesophageal echocardiography (TEE) was used to determine myocardial contractility. Permissive hypercapnia resulted in significant decreases in systemic vascular resistance (SVR) and increases in cardiac output (Q). Myocardial contractility decreased in both groups but significantly less in the pH-corrected group (approximately 10%) than in the pH-uncorrected group (approximately 18%, p < 0.05). Mean arterial pressure decreased and mean pulmonary arterial pressure increased significantly only in the pH-uncorrected group. All values returned to baseline conditions 1 h after permissive hypercapnia was terminated. Our study demonstrates a reversible depression of myocardial contractility and hemodynamic alterations during rapid permissive hypercapnia which were attenuated by buffering with THAM. This may have applicability to the clinical strategy of permissive hypercapnia and allow the benefit of decreased airway pressures to be realized while minimizing the adverse hemodynamic effects of hypercapnic acidosis.