An increased frequency of alpha-1-antitrypsin deficiency (AATD) has been reported in patients with hepatocellular carcinoma (HCC) in Scandinavia and England. Using a specific immunoperoxidase technique for alpha-1-antitrypsin (AAT) and periodic acid-Schiff (PAS) with and without diastase predigestion, the authors examined nonneoplastic autopsy liver tissue from 58 black southern African patients with HCC and from 54 controls. No periportal PAS-positive diastase-resistant globules containing AAT (specific for AATD) were found in liver tissue from either group. A finely granular diffuse cytoplasmic AAT staining (not removed by diastase predigestion) was present in hepatocytes in a "checkerboard" pattern within the lobule in 33 (57%) HCC patients and in 20 (37%) controls (P greater than 0.1), and was particularly prominent adjacent to tumor in 11 HCC patients. Alpha-1-antitrypsin was present in neoplastic cells in 18 of the 40 HCC examined (45%). These findings suggest no major role for AATD in the etiology of HCC in southern Africa.