Dupuytren's disease (DD) is a fibromatosis characterized by non-malignant transformation of palmar fascia leading to permanent contraction of one or more fingers. Despite the extensive knowledge of its clinical pathogenesis, the aetiology of this disease remains obscure. In the present paper, we report for the first time on the proteomic profiling of diseased versus unaffected patient-matched palmar fasciae tissues from DD patients using two-dimensional gel electrophoresis coupled with mass spectrometry analysis. The herein identified proteins were then used to create the protein-protein interaction network (interactome). Such an integrated approach revealed the involvement of several different molecular processes related to DD progression, including extra- and intra-cellular signalling, oxidative stress, cytoskeletal changes, and alterations in cellular metabolism. In particular, autocrine regulation through ERBB-2 and IGF-1R receptors and the Akt signalling pathway have emerged as novel components of pro-survival signalling in Dupuytren's fibroblasts and thus might provide a basis for a new therapeutic strategy in Dupuytren's disease.