Methods to guide fluid therapy in spontaneously breathing patients are scarce. No studies have reported the accuracy of end-tidal CO2 (ET-CO2) to predict volume responsiveness in these patients. We sought to evaluate the ET-CO2 gradient (ΔET-CO2) after a passive leg rise (PLR) maneuver to predict volume responsiveness in spontaneously breathing healthy adults. We conducted a prospective study in healthy adult human volunteers. A PLR maneuver was performed and cardiac output (CO) was measured by transthoracic echocardiography. ET-CO2 was measured with non-invasive capnographs. Volume responsiveness was defined as an increase in cardiac output (CO) > 12% at 90 s after PLR. Of the 50 volunteers, 32% were classified as volume responders. In this group, the left ventricle outflow tract velocity time integral (VTILVOT) increased from 17.9 ± 3.0 to 20.4 ± 3.4 (p = 0.0004), CO increased from 4.4 ± 1.5 to 5.5 ± 1.6 (p = 0.0), and ET-CO2 rose from 32 ± 4.84 to 33 ± 5.07 (p = 0.135). Within the entire population, PLR-induced percentage ∆CO was not correlated with percentage ∆ET-CO2 (R2 = 0.13; p = 0.36). The area under the receiver operating curve for the ability of ET-CO2 to discriminate responders from non-responders was of 0.67 ± 0.09 (95% CI 0.498–0.853). A ΔET-CO2 ≥ 2 mmHg had a sensitivity of 50%, specificity of 97.06%, positive likelihood ratio of 17.00, negative likelihood ratio of 0.51, positive predictive value of 88.9%, and negative predictive value of 80.5% for the prediction of fluid responsiveness. ΔET-CO2 after a PLR has limited utility to discriminate responders from non-responders among healthy spontaneously breathing adults.