We have investigated the ability of metastatic cells to produce the macrophage cytokine, TNF-alpha/cachectin, as these cells have macrophage-like properties such as infiltration and migration. We looked for TNF-alpha/cachectin in three tumor cell lines derived from human malignant melanomas and six co-cultivated malignant melanomas derived, in vitro, from these three cell lines plus angioma fibroblasts. Immunohistochemistry with an anti-TNF-alpha/cachectin monoclonal antibody showed that TNF-alpha/cachectin was produced by two of the three parent melanoma cell lines. All the tumor cells in both the co-cultivated malignant melanomas and their in vitro tumorous nodules produced TNF-alpha/cachectin, even those derived from the melanoma cell line, which originally did not. The results clearly show that TNF-alpha/cachectin can be produced by non-hematopoietic tumor cells. A co-cultivated tumor model prepared from other types of human tumor cell lines promises to provide a useful tool for exploring the relationship between TNF-alpha/cachectin and oncogenesis.