Immunological tolerance to a soluble, partially purified fraction of histocompatibility (H)-2(a) antigen was induced in B10.D2 strain mice. The fraction used was obtained after chromatography on a Sephadex G-150 column. Tolerance of humoral-antibody formation (cytotoxins and hemagglutinins) was observed in mice injected with soluble antigen since birth, but cell-mediated immunity, as measured by skin graft survival, remained intact. Tolerance was shown to be specific for H-2(a) antigens, since treated mice produced a regular humoral-antibody response to H-2(b) antigens. These findings, along with previous observations of the immunogenic and enhancing properties of our partially purified fraction, suggest that the solubilized antigen contains all the major determinants of H-2(a) antigens expressed on lymphoid-cell surfaces.