Purpose To evaluate the effects of acute hypercapnia induced by positive end-expiratory pressure (PEEP) variations at constant plateau pressure ( P plat ) in patients with severe acute respiratory distress syndrome (ARDS) on right ventricular (RV) function. Methods Prospective observational study in two academic intensive care units enrolling 11 adults with severe ARDS (PaO 2 /FiO 2 <150 mmHg at PEEP >5 cmH 2 O). We compared three ventilatory strategies, each used for 1 h, with P plat at 22 (20–25) cmH 2 O: low PEEP (5.4 cmH 2 O) or high PEEP (11.0 cmH 2 O) with compensation of the tidal volume reduction by either a high respiratory rate (high PEEP/high rate) or instrumental dead space decrease (high PEEP/low rate). We assessed RV function (transesophageal echocardiography), alveolar dead space (expired CO 2 ), and alveolar recruitment (pressure–volume curves). Results Compared to low PEEP, PaO 2 /FiO 2 ratio and alveolar recruitment were increased with high PEEP. Alveolar dead space remained unchanged. Both high-PEEP strategies induced higher PaCO 2 levels 71 (60–94) and 75 (53–84), vs. 52 (43–68) mmHg and lower pH values 7.17 (7.12–7.23) and 7.20 (7.16–7.25) vs. 7.30 (7.24–7.35), as well as RV dilatation, LV deformation and a significant decrease in cardiac index. The decrease in stroke index tended to be negatively correlated to the increase in alveolar recruitment with high PEEP. Conclusions Acidosis and hypercapnia induced by tidal volume reduction and increase in PEEP at constant P plat were associated with impaired RV function and hemodynamics despite positive effects on oxygenation and alveolar recruitment ( ClinicalTrials.gov #NCT00236262).