The synergic effects on HeLa cells between 1-hexylcarbamoyl-5-fluorouracil (HCFU), a lipophilic masked compound of 5-fluorouracil (5-FU), and hyperthermia were investigated, with the following results: (1) After the cells had been exposed to the drug at 77 microM for 1, 2 or 3 days, with or without heat (43 degrees C) for 2 h, treatment with HCFU and heat inhibited cell growth by 9.2% on day 3, compared to control cells, HCFU alone, heat alone or the combined treatment with 5-FU plus heat. (2) The cells were exposed to the drugs at 77 microM or heat (43 degrees C) for 15-45 min and the colonies counted on day 14. Combined treatment with HCFU plus heat inhibited the clonogenicity of HeLa cells to 22.4% of findings in the control cells and as compared to findings with other treatments. The combination of 5-FU, n-hexylamine and heat had much the same effect as the combined effect of the treatment of HCFU plus heat. (3) Intracellular levels of the drugs did not increase with hyperthermic treatment. Our findings suggest that it is the hexylcarbamoyl structure of HCFU that relates to the synergic effect between HCFU and hyperthermia. This combination is expected to have positive effects for treating patients with malignancy.