A series of closely related rat brain cell lines that differ in their ability to form tumors has been used to investigate the selectivity of cytotoxic polyunsaturated fatty acids. The colony-formation ability of tumorigenic F4 cells was markedly reduced when the cells were challenged with GLA and EPA. In contrast, the non-tumorigenic revertants were less affected. All retransformed tumorigenic variants exposed to GLA were as sensitive as their parental tumorigenic cells and more sensitive than the non-tumorigenic clones. However, two out of three retransformed tumorigenic variants exposed to EPA were less sensitive than either the parental tumorigenic or non-tumorigenic clones. The addition of ferrous chloride to the culture medium increased the cytotoxicity of GLA in tumorigenic but not in non-tumorigenic variants. These results suggest that tumorigenicity per se is characterized by a high sensitivity to PUFAs exogenously administered at appropriate concentrations and that the sensitivity is fatty acid specific.