Recombinant human activin A, a member of the transforming growth factor-beta superfamily, induced significant cell loss in rodent livers and in primary hepatocyte cultures. Histologically and biochemically the hepatocyte death was mediated by apoptosis, a form of programmed cell death. Male mice were treated with 200 or 500 micrograms recombinant human activin A/kg body wt/day for up to 3 days by means of a subcutaneously implanted minipump. Livers were taken for light and electron microscopy, DNA isolation and in situ nick end-labeling. Primary cultures of rat hepatocytes were treated with 10 ng/ml recombinant human activin A for 24 hr before being harvested for electron microscopy and DNA isolation. Infusion of activin A evoked dose-dependent loss of liver mass due to the atrophy and death of hepatocytes around the central vein. Morphologically, the dying cells demonstrated all the characteristic nuclear and cytoplasmic features of apoptosis. Low molecular weight DNA isolated activin A-treated intact livers and primary cultures exhibited the typical oligosomal ladder. Nick end-labeling of DNA in situ confirmed that virtually all topographical apoptotic hepatocytes had fragmented DNA. The currently accepted criteria for apoptosis (i.e., specific morphological alterations and internucleosomal clipping of DNA) were evident in activin A-treated hepatocytes both in vitro and in vivo, leading to the conclusion that cell loss occurs mainly through apoptosis. These observations suggest that activin A may be important in hepatic homeostasis.