INTRODUCTION: The beneficial effect of low tidal volume (TV) ventilation strategy on mortality in patients with acute respiratory distress syndrome (ARDS) has been attributed to the protective effect on ventilator-induced lung injury, and yet its effect on cardiovascular function might also play an important role. The aim of this study was to assess whether low TV ventilation improves cardiac output and oxygen delivery compared with high TV ventilation strategy in patients with ARDS. METHODS: In this crossover randomized clinical trial 16 ARDS patients were recruited in an intensive care unit at a university-affiliated hospital. Each patient was ventilated for 30 min with low (6 mL/kg) and 30 min with high (12 mL/kg) TV. The two experimental periods, applied in random order and with allocation concealment, were separated by 30 min of basal ventilation. Minute ventilation was constantly maintained by appropriate respiratory rate changes. RESULTS: Compared with high TV ventilation, low TV ventilation showed decreased pH (7.37 vs. 7.41, P = 0.001) and increased PaCO₂ (49 vs. 43 mmHg; P = 0.002). Cardiac index and oxygen delivery index were increased with low compared with high TV ventilation (3.9 vs. 3.5 L.min⁻¹.m⁻², P = 0.012, and 521 vs. 463 mL.min⁻¹.m⁻², P = 0.002, respectively), while oxygen extraction ratio decreased (0.36 vs. 0.44, P = 0.027). In four patients oxygen extraction ratio was >0.5 during high TV but not during low TV strategy. The magnitude of the change in cardiac index was positively associated with PaCO₂ variation (P = 0.004), while it was unrelated to the magnitude of changes in TV and airway pressure. The decrease of cardiac index was predicted by PaCO₂ reduction, with and area under ROC curve of 0.72. CONCLUSIONS: Our findings suggest that a low TV ventilation strategy increases cardiac index and oxygen delivery, thus supporting the hypothesis that the beneficial effect of low TV ventilation in patients with ARDS could be partially explained by hemodynamic improvement. In other words, low tidal volume ventilation could be protective also for the cardiovascular system and not only for the lung. The slight increase of PaCO₂ during low TV ventilation seems to predict the increase of cardiac index. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00713713.