Growth of Mycobacterium kansasii TMC 1203 in B6D2 F1 hybrid mice was associated with increased splenic cellular proliferation, hyperplasia and the generation of non-specific antibacterial resistance. Both responses were dose dependent; the larger the inoculum, the more rapid and extensive the cellular response. However, such mice were still unable to reduce the mycobacterial load within the tissues, apparently because of their inherent resistance to inactivation by immunologically activated macrophages. On the other hand, mice infected with the non-persistent strain of M. kansasii 1214 exhibited only a transient increase in non-specific (anti-listeria) resistance which rapidly declined as the number of viable mycobacteria within the spleen fell below an arbitrary threshold level. Mice infected with either M. kansasii 1203 or 1214 could be immunized with sheep red blood cells (SRBCs), an unrelated T cell-dependent antigen. The humoral (PFC) response was not affected by the mycobacterial load within the spleen. However, the delayed footpad swelling reaction was severely depressed. The latter could be restored merely by increasing the size of the intravenous sensitizing inoculum 100-fold. The present study indicates that mice chronically infected with M. kansasii are not severely immunosuppressed (as had been inferred from earlier in vitro lymphoproliferation studies) but are fully capable of responding to appropriate in vivo stimuli.