Cells from the spontaneous metastatic TS/A mammary adenocarcinoma of a BALB/c mouse were transfected with the murine γ‐interferon (IFN‐γ) gene. Six clones (IFN‐γ clones) releasing between 2 and 6,000 international units (IU) of IFN‐γ/ml culture medium, were compared to TS/A parental cells (TS/A‐pc) and to cells transfected with neomycin resistance gene only (NEO cells). Autocrine IFN‐γ up‐regulated membrane expression of H‐2 class‐1 and Ly‐6 glycoproteins, but did not alter cellular proliferation in vitro. All IFN‐γ clones gave rise to progressive tumors with a growth rate significantly slower than that of tumors induced by TS/A‐pc and NEO cells, and inversely correlated with the amount of IFN‐γ secreted. TS/A‐pc and NEO tumors displayed a marginal reactive infiltrate, whereas those formed by IFN‐γy clones were massively infiltrated mostly by macrophages. In T‐ and NK‐deficient mice the growth of tumors formed by I FN‐y clones was not enhanced. In vitro tests showed that IFN‐γ clone cells were markedly more lysed by macrophages than TS/A‐pc and NEO cells, while they remained poorly sensitive to NK and LAK cells. These data as a whole suggest that the development of solid tumors by IFN‐γ clones is primarily hampered by macrophages and not by T‐lymphocytes or NK cells. When spontaneous metastatic ability was compared, 2 IFN‐γ clones releasing 2‐4 IFN‐γ lU/ml were significantly more metastatic, while most IFN‐γ clones appeared to be as metastatic as NEO cells. By contrast, following intravenous challenge, all IFN‐γ clones produced 5‐10 times more experimental metastases than NEO cells. The higher metastatic ability of IFN‐γ clones was attributed to increased resistance to NK cells since, in NK‐depleted BALB/c mice, metastatic spread of IFN‐γ clones was not enhanced, whereas a 50‐fold increase in the number of metastases was found upon injection of NEO cells.