Intravenous injection of rabbit anti-asialo-GM1 serum, an antiserum previouslY shown to eliminate splenic natural killer (NK) activity in vitro, profoundly depressed NK activity in CBA, DBA/2 and BALB/c nu/nu mice. The effect on NK activity was selective, as treatment of mice with anti-asialo-GM1 serum did not affect the development of other cytotoxic cells including cytotoxic macrophages following injection of poly I:C, or cytotoxic T cells in response to allogeneic cells. The role of NK cells in controlling tumor cell growth was investigated using an NK-sensitive (cl 27v-1C2) and an NK-resistant (cl 27av) subline of the murine lymphoma L5178Y. Initial studies showed that cl 27v-1C2 cells were at least 100 times less tumorigenic than were cl 27av cells in both syngeneic DBA/2 mice and BALB/c nu/nu mice. In addition, treatment of DBA/2 mice with poly I:C, which boosted NK activity, markedly depressed the growth of cl 27v-1C2 cells, but not of cl 27av cells. On the other hand, treatment of DBA/2 mice and BALB/c nu/nu mice with anti-asialo-GM1 serum led to a marked increase in tumorigenicity of cl 27v 1C2 cells, but had no effect on the tumorigenicity of cl 27av cells. In addition, the protection against cl 27v-1C2 growth afforded by poly-I:C treatment was abrogated by injection oif anti-asialo-GM1 serum. The possibility that the effects observed were caused by binding of the injected antibodies to the tumor cells was minimized by: (1) using a clone of tumor cells (cl 27v-1C2) that lacks chemically detectable asialo-GM1, and (2) pretreating animals with anti-asialo-GM1 rather than administering antiserum and tumor cells concurrently. These studies provided compelling evidence that NK cells could play an active role in controlling tumor growth. Selective depletion of NK activity by injection of anti-asialo-GM1 serum is a method which would be generally applicable to studying the role of NK cells in disease processes.