We sought to assess variations in pulse oximetry waveform amplitude (ΔP) and peak values (ΔS) separately during passive leg raising (PLR) and challenge plus maintenance crystalloid volume resuscitation over time in mechanically ventilated (MV) patients in shock. Variables were recorded and analayzed using previously described techniques. Findings were compared between the following: at baseline, during passive leg raising (PLR), with 0.9% normal saline administration (or removal), and applying tidal volume (Vt), peak, and mean airway pressure (Paw,peak and Paw,mean, respectively) and positive end-expiratory pressure (PEEP) as covariates in multifactorial logistic regression analysis. Twenty patients with sepsis or septic shock were included in the analysis. Origins of sepsis varied. Their diagnoses upon admission to the intensive care unit included sepsis in nine (45%), septic shock (defined as the need for vasopressors) in nine (45%), and one (5%) rescuscitated from pulseless electrical activity following heroin overdose, all of whom were supported by volume control MV. Eleven patients required vasoactive drugs at the outset, of which seven were on norepinephrine. Three patients required surgical drainage or removal of necrotic tissue. Median ΔP and ΔS decreased, respectively, by 42% and 37% with PLR ( = 0.036 and = 0.061, respectively). There were no significant changes in ΔP and ΔS between PLR and net fluid volume administered. Correction for body weight did not change these relationships. Application of Vt, Paw,peak, Paw,mean, and PEEP did not significantly influence these changes. Hemodynamic repsonse to slow fluid volume administration can be assessed by changes in the pulse oximetry waveform amplitude over time. The effects of mechanical ventilation are negligible.