OBJECTIVES:: To assess renal resistive index variations in response to fluid challenge. DESIGN:: Prospective cohort study. SETTING:: Three ICUs in French teaching hospitals. PATIENTS:: Consecutive patients receiving mechanical ventilation and requiring a fluid challenge. INTERVENTION:: Resistive index measurement before and after fluid challenge. MEASUREMENTS AND MAIN RESULTS:: Renal Doppler was used to measure resistive index and esophageal Doppler to monitor aortic blood flow. Of the 35 included patients, 17 (49%) met our definition for fluid challenge responsiveness, that is, had at least a 10% increase in aortic blood flow. After fluid challenge, mean arterial pressure increased from 73 mm Hg (interquartile range 68-79) to 80 mm Hg (75-86; p < 0.0001) and stroke volume from 50 mL (30-77) to 55 mL (39-84; p < 0.0001). Stroke volume changes after fluid challenge were +28.6% (+18.8% to +38.8%) in fluid challenge responders and +3.1% (-1.6% to 7.4%) in fluid challenge nonresponders. Renal resistive index was unchanged after fluid challenge in both nonresponders (0.72 [0.67-0.75] before and 0.71 [0.67-0.75] after fluid challenge; p = 0.62) and responders (0.70 [0.65-0.75] before and 0.72 [0.68-0.74] after fluid challenge; p = 0.11). Stroke volume showed no correlations with resistive index changes after fluid challenge in the overall population (r = 0.04, p = 0.25), in fluid challenge responders (r = -0.02, p = 0.61), or in fluid challenge nonresponders (r = 0.08, p = 0.27). Stroke volume did not correlate with resistive index changes after fluid challenge in the subgroups without acute kidney injury (AKIN definition), with transient acute kidney injury, or with persistent acute kidney injury. CONCLUSION:: Systemic hemodynamic changes induced by fluid challenge do not translate into resistive index variations in patients without acute kidney injury, with transient acute kidney injury, or with persistent acute kidney injury.