Objective: To evaluate the influence of tidal volume on the capacity of pulse pressure variation (ΔPP) to predict fluid responsiveness. Design: Prospective interventional study. Setting: A 31-bed university hospital medico-surgical ICU. Patients and participants: Sixty mechanically ventilated critically ill patients requiring fluid challenge, separated according to their tidal volume. Intervention: Fluid challenge with either 1,000 ml crystalloids or 500 ml colloids. Measurements and results: Complete hemodynamic measurements including ΔPP were obtained before and after fluid challenge. Tidal volume was lower than 7 ml/kg in 26 patients, between 7-8 ml/kg in 9 patients, and greater than 8 ml/kg in 27 patients. ROC curve analysis was used to evaluate the predictive value of ΔPP at different tidal volume thresholds, and 8 ml/kg best identified different behaviors. Overall, the cardiac index increased from 2.66 (2.00-3.47) to 3.04 (2.44-3.96) l/min m² ( P <0.001). It increased by more than 15% in 33 patients (fluid responders). Pulmonary artery occluded pressure was lower and ΔPP higher in responders than in non-responders, but fluid responsiveness was better predicted with ΔPP (ROC curve area 0.76±0.06) than with pulmonary artery occluded pressure (0.71±0.07) and right atrial (0.56±0.08) pressures. Despite similar response to fluid challenge in low (<8 ml/kg) and high tidal volume groups, the percent of correct classification of a 12% ΔPP was 51% in the low tidal volume group and 88% in the high tidal volume group. Conclusions: ΔPP is a reliable predictor of fluid responsiveness in mechanically ventilated patients only when tidal volume is at least 8 ml/kg. [ABSTRACT FROM AUTHOR]