Background: HVPG measurement is the gold standard for assessing portal hypertension. Many patients decline HVPG measurements due to associated pain. According to previous studies, propofol sedation during HVPG measurements potentially alters HVPG readings. However, opioid analgesics' effects on HVPG await full elucidation. This study aimed to evaluate fentanyl analgesia's effects on HVPG measurement accuracy in patients with cirrhosis. Methods: This prospective, multicenter study included patients with cirrhosis undergoing HVPG measurements, which were performed preanalgesia and under analgesia with fentanyl injection (1.0 or 1.5 μg/kg). Results: Of the 48 enrolled patients with cirrhosis, 23 were administered 1.0 μg/kg fentanyl analgesia during HVPG measurement. The HVPG was 13.4±4.9 mm Hg in preanalgesia and 13.5±5.2 mm Hg under analgesia. HVPG measurement accuracy was not altered after fentanyl analgesia (p = 0.801). The following measures also did not change: heart rate (p = 0.132), mean arterial pressure (p = 0.348), and blood oxygen saturation (p = 0.748); however, respiratory rate (p = 0.001) changes occurred. The Verbal Numerical Rating Score for comfort under analgesia was higher than that in preanalgesia (p = 0.001). Twenty-five patients were administered 1.5 μg/kg fentanyl analgesia during HVPG measurement. The HVPG was 19.5±5.7 mm Hg in preanalgesia and 19.6±5.6 mm Hg under analgesia. HVPG measurement accuracy did not alter after fentanyl analgesia (p = 0.469). Similarly, the following measures did not change: mean arterial pressure (p = 0.871) and oxygen saturation (p = 0.327); nevertheless, respiratory rate (p = 0.015) and heart rate (p = 0.019) changes occurred. The Verbal Numerical Rating Score for comfort under analgesia was higher than that in preanalgesia (p < 0.001). Conclusion: Fentanyl analgesia did not alter HVPG measurement accuracy, and fentanyl improved comfort in patients with cirrhosis during HVPG measurements.