Sensitivity of Syrian hamster cells to the anticarcinogenic action of hamster lymphotoxin obtained from mitogen-stimulated peritoneal lymphocytes depends on the stage of transformation, initiation, and promotion. Dose-response results with 12-O-tetradecanoylphorbol-13-acetate (TPA) plus X-irradiation parallel those obtained on mouse skin. Twice as much lymphotoxin was required to obtain a 50% reduction in TPA-promoted transformation as in nonpromoted transformation, demonstrating a difference in initiated and promoted cell sensitivity to lymphotoxin. In a study of promoted transformation, 48-hr lymphotoxin treatment before or immediately after X-irradiation, or during TPA exposure, caused a persistent inhibition independent of when lymphotoxin was added. The degree of sensitivity of different steps in carcinogenesis as the cells underwent the physiological changes associated with transformation was examined more precisely with 6-hr lymphotoxin treatments. Lymphotoxin treatment before irradiation and TPA caused a transient cellular change. When the cells were initiated within 2 days after lymphotoxin exposure, the induction of promoted transformation was inhibited. Results were similar with nonpromoted transformation. Lymphotoxin became a more effective anticarcinogen as the interval between the lymphotoxin pulse and carcinogen insult or TPA addition was reduced. When added during the last 6 hr of the experiment, lymphotoxin was equally inhibitory, whether or not TPA was present. Thus, lymphotoxin induces an anticarcinogenic physiological state that is short-lived or transient; the temporal relationship between lymphotoxin and carcinogen exposure is important for preventing initiated or promoted transformation.