In studying the histology and immunohistology of tumor-draining lymph nodes, we observed that nodes close to tumor showed reduced paracortical activity relative to those further away. To assess whether this reduction was paralleled by alterations in the functional activity of nodes, we examined the immunocompetence of individually oriented tumor-draining lymph nodes. We assessed the unstimulated activity of lymph node lymphocytes and their responses to phytohemagglutinin, interleukin 2, and one-way alloantigenic stimulation (mixed lymphocyte reaction) in vitro. Regional nodes from patients with malignant melanoma or breast cancer were classified as proximal, intermediate, or distal relative to tumor. Node groups with and without tumor metastases in them were studied. Significant variations in [3H]thymidine uptake were noted with the unstimulated and stimulated lymphocytes of different lymph nodes from the same individual. Nodes near to tumor were less responsive than those located further away; some of the latter showed relative immunostimulation. Tumor-draining node groups thus demonstrated a nonrandom variation in the strength of reaction of individual nodes. There are zones of low and high lymph node reactivity, related to the position of each node relative to tumor. Tumor-derived immunosuppressive products and/or immunoregulation down-regulates lymph node functional activity, creating conditions that may permit the survival of tumor cells and the establishment of metastases. It is suggested that immunosuppression of nodes nearest to tumor may facilitate the early establishment of metastases.