BACKGROUND: Non-selective beta-blocker (NSBB) therapy is the treatment of choice for primary prophylaxis of cirrhotic patients with high-bleeding risk esophageal varices (HRV). The hemodynamic response to NSBB is assessed by the measurement of the hepatic venous pressure gradient (HVPG). Recently, liver and spleen stiffness measurements (LSM and SSM) were proposed as non-invasive surrogates of HVPG. We aimed to evaluate LSM and SSM changes for assessing hemodynamic response in these patients. METHODS: Cirrhotic patients with HRV were prospectively enrolled and evaluated at our Department before starting NSBB and after 3 months. Correlation between changes (delta) of HVPG after NSBB treatment and those of LSM or SSM by transient elastography was performed. RESULTS: From the initial 59 patients considered for the study, 20 were finally included in the analysis. Fifteen (15) patients reached hemodynamic response to NSBB according to HVPG. Changes in LSM did not correlate with changes in HVPG (r = 0.107, p value = 0.655), unlike changes in SSM (r = 0.784, p value < 0.0001). Delta SSM presented excellent accuracy in identifying HVPG responders (AUROC 0.973; 95% CI 0.912-1). The best cut-off for delta SSM to identify responders was -10% (sensitivity 100%, specificity 60%, NPV 100% and PPV 90%). CONCLUSIONS: SSM could be a reliable non-invasive test for the assessment of hemodynamic response to NSBB therapy as primary prophylaxis for HRV. Similar to HVPG, SSM reduction >/= 10% is able to assess hemodynamic response.