The cytotoxicity of the topoisomerase-I inhibitors, camptothecin and topotecan, toward the SCC-25 human head-andneck squamous-carcinoma cells and the SCC-25/CDDP sub-line made resistant to cis-diamminedichloroplatinum(ll) was assessed alone and in combination with radiation. Topotecan was less cytotoxic than camptothecin in cell culture and the SCC-25/ CDDP cell line was more sensitive to either topoisomerase-I inhibitor than was the parental SCC-25 cell line. Both camptothecin and topotecan were effective radiation sensitizers of hypoxic SCC-25 and SCC-25/CDDP cells under normal pH or acidic pH conditions. Sensitizer-enhancement ratios ranged between I .5 and I .6 for hypoxic SCC-25 cells and between I .3 and 1.5 for hypoxic SCC-25/CDDP cells. When the ability of campothecin or topotecan to sensitize the FSallC fibrosarcoma to single-dose radiation was assessed using the tumor-cellsurvival assay, a sensitizer-enhancement ratio of I .2 was found with each drug. However, using tumor growth delay of the FSallC fibrosarcoma to determine the effect of camptothecin or topotecan to enhance the efficacy of a daily fractionated radiation regimen, topotecan produced a sensitizer-enhancement ratio of I .4, while that for camptothecin was I .2. These results indicate that topoisomerase-l inhibitors may retain activity in CDDP-resistant cells and may be effective adjuncts to radiation therapy.