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Immune-associated molecules play important roles in cancer development and progression. The aims of this study were to determine the diagnostic utility of uric acid (UA) and soluble MHC class I chain-related molecules A (sMICA) and B (sMICB) in pancreatic ductal adenocarcinoma (PDAC) compared with those of cancer antigen 19-9 (CA19-9), the most commonly available tumor marker for PDAC. We evaluated serum levels of UA, sMICA and sMICB along the carcinogenic process of PDAC obtained from 148 individuals composed of normal (= 70), chronic pancreatitis (= 23) and PDAC (= 55), and compared them with those of CA19-9. We also evaluated the correlations of these biomarkers with tumor size, resectability or TNM stage, and tested logistic regression to ascertain the potential usability of these markers for the detection of PDAC. We also investigated the correlations among these biomarkers. Serum UA, sMICA and sMICB differed significantly according to groups (Kruskal–Wallis, < 0.05), and were closely correlated with the development of PDAC. Serum sMICA were correlated with distant metastasis and sMICB were correlated with unresectability. Sensitivity and specificity of sMICA and sMICB were higher than CA19-9, and a multi-maker panel using all tested markers (UA, sMICA, sMICB and CA19-9) demonstrated the best potential for detecting PDAC (94.2% sensitivity at 93.3% specificity). The three tested markers also showed added diagnostic potentials to overcome the limitation of CA19-9 by differentiation of PDAC from non-cancerous conditions when CA19-9 is inappropriate. In conclusion, serum UA, sMICA and sMICB might be useful screening or differential diagnostic biomarkers for PDAC to complement CA19-9. (Cancer Sci 2011; 102: 1673–1679)