The in vitro cytotoxic activity of a 1 hr-treatment with lonidamine alone or combined with hyperthermia was investigated on primary cultures obtained from 12 human malignant melanomas and 9 lung carcinomas. The study was carried out by an antiproliferative assay based upon the inhibition of incorporation of 3H-thymidine into DNA of cells grown in agarose for 4 days. Under normothermic conditions the drug did not have any cytotoxic effect on either tumor type. Hyperthermia alone also failed to influence proliferation of melanoma and lung carcinoma cells. When the same tumors were exposed to lonidamine at 42 degrees C, there was significant enhancement of drug activity in both tumor types. There was also a synergistic interaction in a percentage of tumors, which increased as a function of drug concentration.