Background: We aimed to evaluate the ability of inferior vena cava (IVC) distensibility using the transhepatic approach to predict fluid responsiveness in mechanically ventilated patients with septic shock after emergency laparotomy. Methods: This prospective observational study included mechanically ventilated paralyzed adult who had septic shock after emergency laparotomy. The IVC dimensions were measured through the transhepatic and subxiphoid approaches. The fluid responsiveness was confirmed with >15% increase in cardiac output after 500 mL of fluid bolus. The outcomes were the ability of transhepatic (primary outcome) and subxiphoid approach to predict fluid responders using the area under the receiver operating characteristics curve analysis. The gray zone for the two approaches was calculated. Results: Data from 51 patients were analyzed, and the number of fluid responders was 30 of 52 (58%). The transhepatic approach was feasible in all patients, whereas the subxiphoid approach was only feasible in 42 patients. The area under the receiver operating characteristics curve (95% confidence interval) for the transhepatic IVC distensibility was 0.88 (0.76-0.95), and it was comparable with that of the subxiphoid approach (0.81 [0.66-0.92], P = 0.417). The gray zone for the transhepatic IVC distensibility was 17% to 35% including 24 of 51 patients (47%), whereas the gray zone for the subxiphoid IVC distensibility was 13% to 34% including 18 of 42 patients (43%). Conclusion: In conclusion, the transhepatic approach for evaluation of IVC distensibility showed good accuracy in predicting fluid responsiveness in patients with septic shock after emergency laparotomy. The transhepatic approach showed the same accuracy as the subxiphoid approach with the advantage of being feasible in larger number of patients.