The ultrastructural pattern of the anti-tumor response elicited by interleukin-4 (IL-4) was investigated by using a spontaneous mammary adenocarcinoma (TS/A) unable to elicit protective immunity in syngeneic BALB/c mice as suggested by a variety of preimmunization-challenge experiments. A subcutaneous lethal challenge of TS/A tumor cells was inhibited in a significant number of BALB/c mice receiving recombinant murine IL-4 injected daily for 10 days around the tumor-draining lymph node. Tumor rejection was mainly the result of direct membrane and cytoplasmic damage to tumor cells by eosinophils, neutrophils and macrophages that deeply penetrated the proliferating tumor mass. Lymphocytes and fibroblasts participated in the reaction by interacting with tumor cells, granulocytes and each other. The most frequent cell interactions in the peri- and intra-tumoral areas and in the tumor-draining lymph nodes are illustrated. The efficiency with which the IL-4-activated reaction leads to tumor inhibition and induction of a T-lymphocyte-dependent tumor-specific immune memory appears to depend on interactions between distinct leukocytes.