Arsenic (As) is a toxic environmental contaminant and potential human carcinogen. Chronic intake of arsenic-contaminated water leads to arsenicosis that is a major public health problem in many parts of the world, including India and Bangladesh. Thus, the early detection of arsenic toxicity will greatly benefit patients. However, the detection of arsenicosis needs to be done early before onset of severe symptoms in which case the tools used for detection have to be both sensitive and reliable. In this context, the present study investigated plasma proteome changes in arsenic-exposed Labeo rohita, with the aim of identifying biomarkers for arsenicosis. Changes in the plasma proteome were investigated using gel-based proteomics technology. Using quantitative image analysis of the 2D protein profiles, unique protein spots were identified from the plasma proteome by MALDI-TOF-TOF-MS. Unique proteins identified included Apolipoprotein-A1 (Apo-A1), α-2 macroglobulin-like protein (A2ML), and transferrin. Highly up-regulated protein spots identified in plasma from arsenic-exposed fish were liver-specific, including Apo-A1, and A2ML consistent with liver damage. It is proposed that a combination of these proteins could serve as useful biomarkers of hepatotoxicity and chronic liver disease due to arsenic exposure.