Summary: The variation in the dose of ultracentrifuged human γ globulin (HGG) needed to produce an unresponsive state in different strains of inbred mice was shown to be the result of differences in the efficiency with which these strains process the trace amount of aggregated material remaining. Although mice from both C57BL/6J and BALB/cJ strains remove the aggregated material from the vascular fluids following injection of HGG, the BALB/cJ mice appear to process this material efficiently, and an immune response rather than an unresponsive state results. Conversely, C57BL/6J mice appear to process the aggregated material inefficiently, thus permitting the induction of unresponsiveness to the non-aggregated (tolerogenic) material. When the trace amount of aggregates was removed by salt fractionation, mice from both strains became unresponsive to small doses of HGG. The tolerogenic, deaggregated HGG was rendered immunogenic by chemical aggregation. The dose of HGG to which mice become unresponsive appears to be controlled by a genetic mechanism involving more than one gene. C57BL/6J mice readily became unresponsive following injections of deaggregated γG isolated from normal rabbit serum, but made an antibody response to γG (ALG) isolated from the sera of rabbits immunized with mouse thymus cells. Mice made unresponsive to deaggregated RγG did not lose their unresponsive state following injection of ALG. Within the limits of the test system that was used, no low-dose unresponsive state was observed in C57BL/6J and BALB/cJ mice injected with ultracentrifuged HGG.