A 45-year-old female was admitted to our ICU with severe ascites, and septic shock due to an obstructive ureteric stone. Despite an F(IO(2)) of 1.0, high PEEP, and multiple recruitment maneuvers, it was challenging to obtain an S(pO(2)) > 85% after the patient was turned. We inserted an esophageal balloon to determine whether the abdominal pressure was affecting lung compliance. PEEP was guided to a level of 32 cm H(2)O to achieve a transpulmonary pressure of 0 cm H(2)O. Within 6 hours there was significant oxygenation improvement: P(aO(2))/F(IO(2)) increased from 80 mm Hg to 244 mm Hg, and oxygenation index decreased from 35 to 18. At 48 hours, P(aO(2))/F(IO(2)) was 382 mm Hg and oxygenation index was 7. Paracentesis of approximately 5 L assisted with weaning. Subsequent PEEP changes were guided by transpulmonary pressure. She was weaned from mechanical ventilation within 10 days, with no adverse sequelae associated with very high PEEP.