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Background & Aims: Therapeutic plasma exchange (PEX) has shown potential in improving transplant-free survival in acute liver failure (ALF) however the mechanism of action is not understood. This exploratory study aimed to elucidate the circulating proteomic changes associated with PEX in ALF to provide insight into mechanisms underlying the benefit of this therapy., Methods: Consecutive patients admitted with ALF between June 2019 and August 2020 were enrolled. Patients received either standard medical treatment (n = 5) or PEX (n = 5). Plasma samples were collected at multiple time points and analysed using the Olink Proximity Extension Assay. Comparative analyses included healthy controls and Octaplas batches., Results: Biomarker results were available for 54 samples: Octaplas batches (n = 7), healthy controls (n = 6), ALF-standard medical treatment (n = 8), and ALF-PEX (n = 33). Proteomic analysis of 177 biomarkers revealed marked baseline differences between ALF and healthy controls, with ALF patients exhibiting lower levels of proteins secreted by the liver and higher levels of inflammatory cytokines and growth factors. Longitudinal analysis showed several distinct patterns with PEX. Proteins including carboxylesterase-1, hepatocyte growth factor, fetuin B, IL-6 and IL-10 showed differential expression patterns longitudinally, indicating some of the potential underlying mechanisms and therapeutic effects of PEX., Conclusions: PEX in ALF patients leads to dynamic proteomic changes, reflecting its multifaceted role in modulating inflammation, liver regeneration and replacing essential proteins. These findings provide insight into some of the changes in circulating blood proteins and underlying mechanisms of PEX., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)