The authors investigated whether the pulse pressure power spectrum (PPPS) could predict the effect of volume expansion (VE) in shock patients under mechanical ventilation without sedation. The PPPS within a frequency band of 0.15 to 0.75 Hz was developed with an animal model using nine domesticated piglets simulating acute hemorrhagic shock and then validated in 17 nonsedated mechanically ventilated shock patients. Hemodynamic parameters were recorded before and after VE. In the animal model under anesthesia and pressure-controlled ventilation, the absolute and proportional change of cardiac index after VE (DeltaCI and DeltaCI%) positively correlated with the square root of PPPS (SQRT-PPPS, r(2) = 0.34 and r(2) = 0.72, respectively). The correlations were weaker with PP variation averaged on 120-s sliding window (PPV120, r(2)= 0.27 and r(2)= 0.64, respectively) and PPV30 (r(2)= 0.28 and r(2)= 0.63, respectively) under pressure-controlled level 10 cmH(2)O. Defining the volume responder as DeltaCI% greater than or equal to 15%, the area under the receiver operating characteristic curve (AROC) were equivalent for SQRT-PPPS (0.91), PPV120 (0.86), and PPV30 (0.85). For the 17 patients who had spontaneous breathing movements under assisted pressure-controlled ventilation, the DeltaCI and DeltaCI% positively correlated with SQRT-PPPS (r(2) = 0.35 and r(2)= 0.73, respectively). The correlations were weaker with PPV120 (r(2)= 0.27 and r(2) = 0.42) and PPV30 (r(2) = 0.27 and r(2)= 0.40). The AROC were 0.78 for SQRT-PPPS (P = 0.047), 0.71 for PPV120 (P = 0.131), and 0.69 for PPV30 (P = 0.185). In mechanically ventilated shock patients, SQRT-PPPS predicts volume responsiveness without the need for sedation to prevent spontaneous breathing movements.