The present study was performed to further evaluate the possible in vivo involvement of natural killer (NK) cells in host resistance against tumors. Selective depression of NK activity in Wistar Furth rats was induced by i.p. or i.v. injection of rabbit anti-asialo GM1. This antiserum has previously been shown to produce a decrease in NK activity and a parallel increase in tumor growth in mice. In the present study, rats treated with this antibody showed a parallel decrease in NK activity and in the frequency of large granular lymphocytes (LGL) in the spleen and peripheral blood, indicating that the antiserum-induced depression of NK activity in these sites was probably caused by an elimination of most effector cells. To further determine the possible role of rat LGL in tumor rejection in vivo, we studied LGL involvement in the rapid clearance of radiolabeled tumor cells from the lungs, an assay previously shown to correlate well with in vitro NK activity. Animals treated with anti-asialo GM1 antiserum were found to have a substantial decrease in the in vivo rate of clearance of tumor cells from the lungs. Furthermore, the adoptive transfer of a highly enriched population of LGL into NK-depressed animals 2 hr before tumor challenge, partially restored their cytotoxic activity against established cell lines in vitro and their ability to eliminate radiolabeled cells from the lungs. These results provide direct support for the hypothesis that NK cells are involved in in vivo resistance to tumors, particularly in the elimination of potentially metastatic tumor cells from the circulation and capillary beds.