Administering moderate (milligram) amounts of antigen to a guinea pig immunized with thatntigen leads to a transient loss of all delayed hypersensitivity (DH) responses in that animal. In this study, we demonstrate that this "desentization" can be prolonged for 10 days by repeated injection of antigen. At this time, tolerance to the desensitizing antigen develops in both the humoral and cellular systems of the immune response and DH responsiveness to other antigens returns. Repeated cycles of sensitization and desensitization produce repeated episodes of generalized anergy. Neither cells nor serum from desensitized animals could be shown to exert a suppressor effect when transferred to immunized animals and the cells responded normally to antigen and mitogen in tissue culture. The best generalized depression of DH was seen in those animals producing the best DH before desensitization. The inability of antigen to react with tolerant cells to produce desensitization suggests that this phenomenon is an active rather than a passive one and may represent an exaggeration of a normal regulatory mechanism for DH triggered by a regimen of antigen administration that activates suppressor cells to produce a systemic effect.