The effects of in vivo administration of monoclonal antibodies directed against the two major mature T cell subsets of miniature swine have been examined. Antibody 76–2–11, specific for the porcine CD8 cell-surface antigen, caused elimination of CD8+ T cells from the peripheral lymphocyte pool by 4–6 days following a single intravenous infusion. This depletion persisted while excess antibody was detectable in the serum and CD8+ cells returned rapidly to normal levels following the disappearance of serum antibody. In vitro functional assays performed on PBL during the period of depletion showed no effect on proliferative responses but a profound inhibition of ability to generate CTL. In contrast, administration of monoclonal antibody 74–12–4, specific for CD4+ porcine T lymphocytes, caused no consistent change in the level of CD4+ cells in the peripheral lymphocyte pool. By flow microfluorometry, CD4+ peripheral lymphocytes were found to be coated with the antibody, and there also was excess antibody in the serum for at least 4 days in two of the three animals treated. No effects on in vitro proliferative responses or generation of CTL in vitro were observed, even during the period of excess circulating antibody. Treatment with both antibodies was tolerated well by all animals. These findings are similar to those that have been found in clinical studies of monoclonal antibody treatment and suggest that the pig will provide a large animal preclinical model in which the effects of in vivo treatment with monoclonal antibodies on parameters of transplantation immunity can be tested.