Background: Tidal volume challenge pulse pressure variation (TVC-PPV) is considered one of the recent reliable dynamic indices of fluid responsiveness (FR); also, passive leg raising (PLR)-induced changes in cardiac output (CO) detected by echocardiography are considered a reliable reversible self-fluid challenge test; many patients share eligibility for both tests. Objectives: The study aimed to compare the sensitivity and specificity of both tests for the prediction of FR in mechanically ventilated patients with hemodynamic instability. Methods: We studied 46 patients. Hemodynamic parameters including PPV and CO (detected by velocity time integral (VTI) using echocardiography) recorded at tidal volume (VT) of 6 mL/kg/ideal body weight (IBW) in semi-recumbent position then recorded again after one-minute increase in TV from 6 to 8 mL/kg/IBW then recorded with PLR at TV of 6 mL/kg/IBW and finally with actual volume expansion in semi-recumbent position by 4 ml/kg bolus of crystalloid solution to define actual responders with increase of cardiac output of 15% or more. Results: Sixteen patients were responders, and thirty patients were nonresponders; responders had significant increase in PPV with TVC 6 to 8 ml/kg/IBW with best cutoff value of 3.5 with a sensitivity of 93.8% and a specificity of 93.9%. PLR test-induced changes in CO had a sensitivity of 93.9% and a specificity of 86.7% with statistically best cutoff value of 6.5% increase in CO, but sensitivity was 75% at cutoff value of 10% increase in CO. Other parameters like PPV, PPV changes with PLR test, and PPV changes with fluid expansion were less sensitive indicators. Conclusion: FR in patients with hemodynamic instability and mechanically ventilated with low tidal volume strategy can be efficiently predicted when PPV increases more than 3.5 with tidal volume challenge and when PLR induces 6.5% increase in CO monitored through VTI method by Doppler echocardiography, and both tests are equally reliable.