Abstract Purpose: The prognosis of patients with unresectable hepatocellular carcinoma (uHCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early clinical hepatic decompensation (CHD) within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with Atezolizumab plus Bevacizumab or Sorafenib. Patients and Methods: Individual patient data from IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risks analysis against HCC radiological progression. Early CHD and HCC radiological progression were assessed as predictors of OS by time-dependent Cox model. Results: The 3- and 12-month rates of CHD were 7% and 12%, respectively, while the 3- and 12-month rates of HCC radiological progression were 23% and 52%. Albumin-bilirubin(ALBI)grade 2 (Sub-distribution hazard ratio[sHR] 1.79, 95%CI 1.01-3.19, p=0.049), INR(sHR 1.97, 95%CI 1.64-2.37, p<0.001) and presence of neoplastic macrovascular invasion (sHR 2.01, 95%CI 1.14-3.54, p=0.020) were independently associated with higher risk of CHD. Early CHD(HR 7.56, 95%CI 4.47-12.8) and early HCC radiological progression(HR 5.92, 95%CI 4.03-8.69), as first events, were independently associated with higher mortality. Conclusions: This study provides robust evidence that early CHD is associated with the highest risk of death in patients with uHCC undergoing systemic treatment. Within well-compensated participants, ALBI, INR and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.