['Distinguishing hepatocellular carcinoma (HCC) from adenocarcinoma in fine-needle aspiration biopsies (FNAB) is often diagnostically challenging. Arginase-1 was recently described as a marker of hepatic differentiation in surgical resection specimens. We compared the expression of arginase-1, HepPar-1, and glypican-3 in FNAB of HCC and adenocarcinoma involving the liver.', 'Ninety-eight FNABs including 37 primary or metastatic HCCs (30 well or moderately differentiated and 7 poorly differentiated) and 61 adenocarcinomas involving the liver were evaluated for immunohistochemical expression of arginase-1, HepPar-1, and glypican-3 using formalin-fixed paraffin-embedded cell block material.', 'Arginase-1 was more sensitive (81%) than HepPar-1 (70%) or glypican-3 (54%) for HCC. Arginase-1 more often demonstrated diffuse staining, defined as reactivity in >50% of the tumor, in HCC (21 of 37; 57%) compared with HepPar-1 (15 of 37; 41%) and glypican-3 (12 of 37; 32%). Of the 7 poorly differentiated HCCs, 3 (43%) were immunoreactive for both arginase-1 and glypican-3, whereas only 1 (14%) demonstrated HepPar-1 staining. Arginase-1 expression was identified in adenocarcinomas of pancreatic, colorectal, and breast origin, and reactivity was diffuse in 2 pancreatic adenocarcinomas (2 of 15; 13%).'] Is arginase-1 a more sensitive marker of hepatic differentiation than HepPar-1 and glypican-3 in fine-needle aspiration biopsies?