Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis, where treatment options are limited. As the liver secrets most of the blood plasma proteins, its diseases should affect the plasma proteome. Plasma Proteome Profiling of 48 patients with cirrhosis or NAFLD, revealed eight significantly changing (ALDOB, APOM, LGALS3BP, PIGR, VTN, IGHD, FCGBP and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts with a 2.7-fold expression change in NAFLD and 4-fold change in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE to NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP and LAP3, which all upregulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, Plasma Proteome Profiling can identify potential biomarkers and drug targets in liver disease.