The tumor progression process has been found to be accompanied by various cell membrane modifications. This cell organelle may therefore be considered as a target for drugs directed against tumor cells of advanced cancer. Hyperthermia acts on tumor cells largely, although not only, via an effect on the cell membrane. In the present study, the in vitro effect of hyperthermia on the tumorigenicity of cells derived from two AKR lymphoma variants of malignancy, TAU-39 of low (LM) and TAU-38 of high-malignancy (HM), was compared. The cells of the HM variant were markedly more sensitive to hyperthermic treatment than those of the LM one. Pretreatment of cells at 41 degrees C or 43 degrees C resulted in a more marked delay in tumor appearance in mice injected with the HM than in those inoculated with the LM variant. Moreover, in mice inoculated with cells pretreated at 45 degrees C, long term survivors were found only in those inoculated with the HM variant. These results corroborate our previous data regarding the effect of hyperthermia on metastatic and primary tumor cells of AKR lymphoma as well as the F1 and F10 variants of B16 melanoma.