In order to study the relation between intra- and extrahepatocellular alpha 1-antitrypsin (alpha 1-AT) concentrations in patients with various Pi phenotypes, a prospective series of needle liver biopsies was stained with both periodic acid-Schiff (PAS) and a specific immunoperoxidase technique to demonstrate intracellular alpha 1-AT. Concomitant blood samples from all patients were analysed for alpha 1-AT. Pi phenotypes were determined by isoelectric focusing. Non-globular intrahepatocellular alpha 1-AT can be seen in biopsies from Pi M patients with increased plasma alpha 1-AT concentrations and active liver disease. No evidence was found in this study of 250 patients (including 22 controls) for predisposition toward liver disease in any phenotypic group. PAS or immunoperoxidase staining (or both) for alpha 1-AT demonstrated characteristic globular inclusions in 11 of 15 cases having the Z allele, one case being diffusely positive and three negative. Biopsies from 3 of 207 patients with liver disease and lacking the Z allele had globular inclusions seen with both PAS and immunoperoxidase techniques. alpha 1-AT globules in absence of the Z allele are most often found in elderly patients with severe disease and high plasma alpha 1-AT concentrations.