Natural killer cell-mediated cytotoxicity (NKCC) is one of several possible immune defense mechanisms that may protect against the development of solid-tumor metastases. We have demonstrated that in vitro NKCC can be significantly impaired by both surgical stress and progressive tumor burden. Female C57BL/6 mice received a hindfoot amputation under anesthesia with Nembutal i.p. Twenty-four hr later, amputated and control groups were sacrificed, spleens were harvested, and cytotoxicity assays were performed using 51Cr-labeled Yac-1 lymphoma target cells. In amputated animals, in vitro NKCC was significantly impaired at four effector:target ratios, decreasing by as much as 59%. Nembutal treatment alone caused no significant changes in in vitro NKCC compared to untreated controls. Tumor burden was studied by inoculating the hindfoot pads of C57BL/6 mice with 5 X 10(5) Lewis lung tumor cells. Animal groups were sacrificed 24 hr, 1 week, and 2 weeks after tumor inoculation, and the 51Cr release assay was performed. One day and 1 week of tumor burden mildly stimulated NKCC in vitro; after 2 weeks of tumor burden, when lung metastases were detectable, in vitro NKCC was almost totally suppressed compared with non-tumor-bearing controls. Animals bearing tumor for 1 week and then given amputations showed significantly impaired NKCC in vitro. In vivo, identical animals bearing tumor for 1 week and then given amputations on sacrifice 1 week later were found to have a 71% incidence of lung metastases compared with 38% tumor-bearing unstressed controls. Surgical stress and progressive tumor burden independently and codependently impair NKCC in vitro; this may possibly contribute to the hypermetastatic response observed after surgical stress in this in vivo animal model.