Sepsis being a chief prominent fatal condition in critically ill patients. In septic-shocked patients, the first-line therapeutic intervention is fluid resuscitation in an attempt to improve their cardiac output (COP). However, fluids must be given only if the chance of improving COP exists. So, assessing fluid responsiveness is crucial. To our knowledge, yet no studies comparing the end-expiratory occlusion (EEO) test and the variation of the inferior vena cava (IVC) diameter with respiration (ΔIVC) in hypovolemic cases. So, our aim is to use both tests as indices for responsiveness to fluid in septic mechanically ventilated (MV) patients. The Patients and Method: Thirty-four MV septic patients were enrolled and baseline COP assessment was performed followed by an EEO test applied to each patient, after which, COP was measured to detect the probable responders (defined as an increased COP by ≥ 15%) and non-responders. Then, ΔIVC was assessed for the same patients to predict the probable responders (with ΔIVC >12%) and non-responders. Finally, fluid therapy was initiated as per the guidelines of surviving sepsis campaign (2021) followed by COP re-assessment to determine actual fluid responders\non-responders. Results: 67% of the cases was responding to fluid. Receiver operating characteristic showed areas under curve for EEO and ΔIVC in predicting responsiveness to fluid were 0.597 and 0.925, respectively. EEO (32.4%) was predictive with 47.8% sensitivity and 100% specificity. The ΔIVC (64.7%) was predictive with 91.3% sensitivity and 100% specificity. Conclusion: IVC-respiratory variation showed better values in prediction of response to fluid in MV patients with sepsis than EEO test.