Bivalves, and especially mussels, are very good indicators of marine and estuarine pollution and so they have been widely used in biomonitoring programs all around the world. However, traditional single parameter biomarkers face the problem of high sensitivity to biotic and abiotic factors. In our study, digestive gland peroxisomal enriched fraction of Mytilus edulis (L., 1758) have been analyzed by fluorescent differential gel electrophoresis (DIGE) and mass spectrometry (MS). We have identified several proteomics signatures associated with the exposure to several marine pollutants (diallyl phthalate, PBDE-47, bisphenol-A). Animals collected from North Atlantic Sea were exposed to the contaminants independently under controlled laboratory conditions. One hundred and eleven spots have shown a significantly increase or decrease in protein abundance in the 2-D maps from the groups exposed to pollutants. We have obtained a unique protein expression signature (PES) of exposure to each of those chemical compounds. Moreover, a set of proteins composes a proteomics signature in common to the three independent exposures. It is remarkable that the principal component analysis of these spots shows a discernible separation between groups, and so does the hierarchical clustering into four classes. The fourteen identified proteins by MS participate in alfa- and beta–oxidation pathways, xenobiotics and amino acid metabolism, cell signalling, oxyradical metabolism, peroxisomal assembly, respiration and cytoskeleton. Our results suggest that proteomics signatures could become a valuable tool to monitor the presence of pollutants in field experiments where a mixture of pollutants is often present. Further studies on the identified proteins could provide crucial information to understand possible mechanisms of toxicity of single xenobiotics or mixtures of them in marine ecosystems.