The metabolic relationship between the two major forms of rabbit alpha 1-antitrypsin, F and S, was investigated by using labeling techniques in vivo and in vitro. After the injection of [14C]leucine, the S/F specific-radioactivity ratio showed characteristic changes with time: at 1 h, the ratio was high (1.2-1.4), but by later times (5-7h) it decreased to a value of approx. 1.1. Two different techniques were used to purify alpha 1-antitrypsin for labelling with iodine. The half-lives of the differentially labelled and simultaneously injected F- and S-forms were 68.1 (+/- 7.6 S.D) and 55.3 (+/- 8.1 S.D)h respectively. Combined electrophoretic and gamma-spectrometric studies provided no evidence for metabolic interconversion of the alpha 1-antitrypsin forms in the circulation. These observations suggest that rabbit alpha 1-antitrypsins F and S are, despite their close chemical composition and immunological identity, metabolically independent proteins. Therefore the possibility is raised that alpha 1-antitrypsin synthesis in rabbits is controlled by two autosomal genes or two sets of such genes.