Background: Arginase-1 and HepPar-1 are effective immunohistochemical (IHC) markers for hepatocellular carcinoma (HCC). In this study, we explored the possible efficacy of these stains in diagnosing pancreatic adenocarcinoma (PAD). Study Design: Arginase-1 and HepPar-1 IHC was performed on formalin-fixed, paraffin-embedded fine needle aspiration (FNA) cell blocks (CB) of PAD (n = 46), tissue microarray (TMA) of PAD (n = 33), FNA CB of HCC (n = 44) and TMA of HCC (n = 85). Negative controls without carcinoma were also applied (pancreas CB, n = 7; pancreas TMA, n = 3). Results: PAD CB demonstrated arginase-1 positivity in 0 of 46 cases and HepPar-1 positivity in 7 of 46 cases (15%). PAD TMA demonstrated arginase-1 positivity in 0 of 33 cases and HepPar-1 positivity in 4 of 33 cases (12%). HCC CB demonstrated arginase-1 positivity in 37 of 44 cases (84%) and HepPar-1 positivity in 32 of 44 cases (72%). HCC TMA demonstrated arginase-1 positivity in 75 of 85 cases (88%) and HepPar-1 positivity in 80 of 85 cases (94%). Conclusion: Both arginase-1 and HepPar-1 are effective IHC markers of hepatocellular differentiation. Arginase-1 demonstrates superior sensitivity and specificity compared with HepPar-1 in the diagnosis of HCC. However, both arginase-1 and HepPar-1 have a low sensitivity and a very high specificity for PAD.