The effective treatment of pancreatic cancer relies on the diagnosis of the disease at early stage-- a difficult challenge. One major obstacle in the development of diagnostic biomarkers of early pancreatic cancer has been the dual expression of potential biomarkers in both chronic pancreatitis and cancer. To better understand the limitations of potential protein biomarkers, we employed ICAT (isotope-coded affinity tag) technology and tandem mass spectrometry to systematically study protein expression in chronic pancreatitis. Among the 116 differentially expressed proteins identified in chronic pancreatitis, most biological processes were responses to wounding and inflammation; a finding consistent with the underlining inflammation and tissue repair associated with chronic pancreatitis. Furthermore, 40% of the differentially expressed proteins identified in chronic pancreatitis have been previously implicated in pancreatic cancer, suggesting some commonality in protein expression between these two diseases. Biological network analysis further identified c-Myc as a common prominent regulatory protein in pancreatic cancer and chronic pancreatitis. Lastly, five proteins were selected for validation by western blot and immunohistochemistry. Annexin A2, and IGFBP-2 were overexpressed in cancer, but not in chronic pancreatitis, making them promising biomarker candidates for pancreatic cancer. In addition, our study validated that cathepsin D, integrin beta-1, and plasminogen were overexpressed in both pancreatic cancer and chronic pancreatitis. The positive involvement of these proteins in chronic pancreatitis and pancreatic cancer will potentially lower the specificity of these proteins as biomarker candidates for pancreatic cancer. Together, our study provides some insights into the molecular events in chronic pancreatitis which may lead to diverse strategies for diagnosis and treatment of these diseases.