Despite major deficits in their immune system, SCID, Nude, and NIH III mice reject allo- and xenografts, particularly leukemic cell lines, albeit less readily than immunologically intact mice. Since variation among these immunodeficient mouse strains in rejection of a human lymphoid cell line (CCRF-CEM) parallels splenic non-MHC-mediated cytolytic activity, non-MHC-restricted cytolytic activity may be responsible for retained resistance to leukemic cell transplantation. SCID mice that had the least cytolytic activity accepted 100% of their grafts. The converse was true for NIH III mice that showed the greatest cytolytic activity and were relatively resistant to CEM cell engraftment. Different approaches to ablate NK activity and thus enhance engraftment led to variable results for each strain. A single dose (500 micrograms) of anti-asialoGM1 (AsGM1) markedly reduced NK activity in SCID and NIH III mice by 60 and 40%, respectively. A moderate 20% decrease was seen in Nude mice at this dose. In contrast, gamma irradiation suppressed NK activity by greater than 80% of baseline levels in all three strains. Of importance, total cytolytic activity in immunosuppressed Nude and NIH III mice, although significantly depressed compared to untreated mice of the same strain, still remained higher than that seen in nonimmunosuppressed SCID mice. Enhanced engraftment and systemic dissemination of CEM cells in immunosuppressed mice correlated directly with decreased total splenic cytolytic activity in all three strains. These results have implications for the use of immunodeficient models for transplantation, tumor immunobiology, and engraftment of a human immune system.