Clear cell neoplasms presenting as metastatic hepatic masses may be difficult to differentiate histologically and immunohistochemically from hepatocellular carcinoma (HCC) with prominent clear cell features, especially in small biopsy specimens. In situ hybridization (ISH) for albumin messenger RNA (mRNA) has been previously shown to be sensitive and specific for the detection of hepatocellular differentiation, but its use for the identification of clear cell HCC has not been previously evaluated. Among 309 cases of hepatocellular carcinoma diagnosed at Mayo Clinic between 1985 and 1998, 30 cases (9.7%) with at least 30% (range, 30%-90%; median 60%) clear cells were studied by ISH for albumin mRNA. In addition, immunohistochemical expression of AFP and polyclonal CEA, serum determination of AFP, and histopathologic analyses of the tumor were done. Forty-two clear cell tumors were used as a control group: 21 metastatic clear cell tumors to the liver (14 renal cell carcinomas and 7 adrenal cortical carcinomas) and 21 primary clear cell tumors of the retroperitoneum (10 renal cell carcinomas, 5 adrenal cortical adenomas, 4 adrenal cortical carcinomas, and 2 ovarian carcinomas). ISH for albumin mRNA was reactive in 28 of 30 cases of clear cell HCC (93%). Clear cell HCC expressed AFP (15 cases; 50%) and polyclonal CEA (19 cases; 63%). Tumors expressed either AFP or polyclonal CEA in 23 cases (77%). Elevated serum AFP was present in 24 of 26 cases (92%). These results indicate that ISH for albumin mRNA is a useful method to distinguish clear cell HCC from other clear cell carcinomas metastatic to the liver and clear cell neoplasms in the retroperitoneum.