Nodular regenerative hyperplasia, a disorder characterized by regenerative nodules scattered diffusely throughout the liver without associated fibrosis, is most often recognized at autopsy when the entire liver is available for inspection. Diagnosis by needle biopsy is much more subtle. Because alpha-1-antitrypsin expression by hepatocytes in a variety of liver diseases has suggested that it may represent a marker for regenerative or damaged hepatocytes, we elected to study the expression of alpha- 1 -antitrypsin by immunohisto chemical staining of paraffin-embedded tissue of biopsy material as a possible marker of this diagnosis. Seventeen liver biopsy specimens showing histological features consistent with nodular regenerative hyperplasia were selected and compared with 20 biopsy specimens of the liver without such features. Eight of the diseased cases showed periportal granular alpha- 1-antitrypsin staining as opposed to only one of the healthy biopsy specimens (p < 0.01; Fisher exact test). These results indicate that alpha-1-antitrypsin expression is increased in the regenerating compartment (as opposed to the presumably damaged atrophic portion) of the liver in nodular regenerative hyperplasia and suggest that alpha-1-antitrypsin staining may be useful in confirming the diagnosis of the disease by biopsy specimens.