The most common method of controlling acidemia during lung-protective ventilation is CO₂ removal with an extracorporeal lung assist (ECLA) system. Another possibility to prevent acidemia is based on intravenous (i.v.) application of tris-hydroxymethyl-aminomethane (3 mol/L, THAM) buffer, which can bind hydrogen protons and which can be removed from the body via renal replacement therapy (RRT). We investigated whether RRT combined with predilutional (prefilter) THAM-application provides an alternative to ECLA for a rescue situation. For this, anesthetized pigs, 40 kg of body weight, six animals per group, underwent 5 h of acidemia (pH 7.19-7.24) induced by acid infusion and permissive hypercapnia (low tidal volume ventilation, PaCO₂ 80-90 mmHg). Isovolemic, high-volume hemofiltration (HVHF) was operated with predilutional THAM-infusion for treatment. To evaluate adverse effects of this approach, we set up further groups: HVHF with postdilutional (post-filter) THAM-application; i.v.-THAM without HVHF; normal pH homeostasis with HVHF. Acid-base parameters, hemodynamics, renal function, and lung morphology were investigated. HVHF with predilutional THAM-infusion of 8 mmol/kg/h allowed fast pH normalization, significant reduction in PaCO₂ to 56 mmHg and tolerable hemodynamics. HVHF alone or lower dose i.v. THAM (2 mmol/kg/h) failed to produce a comparable result. A postdilutional THAM infusion reduced hemodynamic tolerability and increased lung edema formation. HVHF in pigs with normal acid-base status resulted in a decreased base excess and urine acidification. In conclusion, predilutional THAM-application and HVHF corrected the acid-base disorder and improved pulmonary hemodynamics. Further studies are necessary to optimize the protocol including the dosage.