SummaryBackground and AimsThe prognostic performance of von Willebrand factor (VWF) may vary across clinical stages of advanced chronic liver disease (ACLD). Therefore, we investigated the evolution of VWF and other biomarkers throughout the full ACLD spectrum and evaluated their stage‐specific prognostic utility.MethodsWe retrospectively included Viennese ACLD patients with available information on hepatic venous pressure gradient (HVPG), C‐reactive protein (CRP)/VWF levels and outcomes. ACLD stages were defined according to D'Amico et al. We included an external validation cohort from Padua.ResultsWe observed gradual increases in VWF throughout ACLD stages. In contrast, HVPG levelled off in decompensated ACLD (dACLD), whereas MELD showed only minor changes in the early stages and CRP did not increase until stage 3. VWF was associated with hepatic decompensation/liver‐related death in compensated ACLD (cACLD) in a fully adjusted model, while it was not independently predictive of ACLF/liver‐related death in dACLD. After backward selection, HVPG/CRP/VWF remained the main predictors of hepatic decompensation/liver‐related death in cACLD. Notably, the performance of the non‐invasive CRP/VWF‐based model was comparable to invasive HVPG‐based models (C‐index:0.765 ± 0.034 vs. 0.756 ± 0.040). The discriminative ability of the CRP/VWF‐based model was confirmed in an external validation cohort using another VWF assay which yielded systematically lower values.ConclusionVWF is the only biomarker that gradually increases across all ACLD stages. It is of particular prognostic value in cACLD, where a CRP/VWF‐based model is equivalent to an invasive HVPG‐based model. Systematic differences in VWF underline the importance of interlaboratory surveys. Moreover, our findings reinforce the notion that, already in cACLD, inflammation is a key disease‐driving mechanism.