Background: The acute hepatic venous pressure gradient (HVPG)‐response to i.v. propranolol predicts outcomes in patients with advanced chronic liver disease (ACLD) and clinically significant portal hypertension (CSPH). While non‐invasive tests (NIT) to monitor non‐selective beta‐blocker (NSBB)‐induced HVPG changes are lacking, spleen stiffness measurement (SSM) has shown promising results as a surrogate for HVPG. This study aimed to assess the correlation between changes in SSM at 100 Hz and HVPG upon acute i.v. propranolol. Methods: ACLD patients with CSPH undergoing paired HVPG and SSM‐100 Hz assessments pre‐ and post‐i.v. propranolol (0.15 mg/kg) at three expert centres between 2019 and 2024 were included. HVPG‐response was defined as a ≥ 10% decrease in HVPG. Results: Ninety‐four patients (63.8% males, median age 57.5 [Q1–Q3: 50.0–65.0] years, BMI 26.6 [22.8–31.1] kg/m ² ) were included. Most had alcohol‐related liver disease (ALD)/metabolic‐associated liver disease (59.6%) or metabolic‐associated steatotic liver disease (11.7%). The median HVPG decreased from 17 (Q1–Q3: 15–20) mmHg to 16 (Q1–Q3: 12–19) mmHg post‐NSBB ( p < 0.001), with 45.7% achieving an acute HVPG‐response. SSM decreased by −8.7 ([Q1–Q3: −19.2; −0.2] kPa, p < 0.001). HVPG‐responders had a significant SSM decrease (−12.4 [Q1–Q3: −26.3; −5.6] kPa, p < 0.001), while non‐responders showed no change. A moderate correlation between relative changes in SSM and HVPG was observed (Spearman's ρ: 0.387; p < 0.001). Relative change in SSM achieved an area under the receiver operating characteristic curve (AUROC) of 0.717 (95% CI: 0.614–0.820, p < 0.001) for diagnosing HVPG‐response. Conclusion: SSM‐100 Hz dynamics are associated with HVPG changes upon i.v. propranolol administration. Although the discriminative ability of changes in SSM was insufficient for clinical use, they may serve as a surrogate of efficacy in clinical trials investigating medical therapies for portal hypertension.

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