The aim of this paper was to determine the clinical significance of the MHC class I chain-related molecule A(MICA) and NKG2D receptor on NK cells in pancreatic cancer. We compared MICA expression in malignant (n = 103), inflammatory (n = 28), and normal (n = 17) pancreatic tissues using immunohistochemistry and assessed serum levels of soluble MICA (sMICA) and NKG2D expression on NK cells in patients with pancreatic cancer (n = 103), in patients with chronic pancreatitis (n = 28), and in healthy volunteers (n = 43). Expression of MICA was detected in 89.3% of pancreatic cancer tissues, whereas fewer were expressed in inflammatory and normal pancreatic tissues. The levels of sMICA were frequently elevated in patients with advanced pancreatic cancer. The elevation of sMICA was associated with down-regulated NKG2D expression and impaired activity of NK cells. The successful tumor resection significantly decreased serum levels of sMICA and increased the NKG2D expression; there was an inverse correlation between change in sMICA levels and that in NKG2D expression. MICA expression, preoperative sMICA levels and NKG2D intensity were found to be independent prognostic factors in resected pancreatic cancer. This study supports the clinical significance of release of MICA for the malignant progression of pancreatic cancer. The successful tumor resection for pancreatic cancer may have a beneficial effect on NKG2D-mediated antitumor immunity. Our results also suggest sMICA and NKG2D expression on NK cells may be useful to identify risk patients at time point of diagnosis.