We investigated the ability of camptothecin (CPT), an inhibitor of topoisomerase (topo) I, and etoposide (VP-16), an inhibitor of topo II, to potentiate X-radiation response and to inhibit the repair of potentially lethal damage (PLDR) and sublethal damage (SLDR) in confluent cultures of a radioresistant (Sk-Mel-3) and a radiosensitive (HT-144) human melanoma cell line. CPT or VP-16 were present both during irradiation and during the subsequent delayed plating period allowed for repair of X-radiation damage. When the direct toxicities of CPT or VP-16 were corrected for, we found that a dose of either drug that killed approximately 15% of the clonogenic cells potentiated the effects of radiation differentially on the cell lines. CPT and VP-16 inhibited the increase in survival brought about by delayed plating of HT-144 but not Sk-Mel-3 cells. In both cell lines, CPT inhibited SLDR but not PLDR. VP-16 also inhibited SLDR in both cell lines, however, in contrast with CPT, it also inhibited PLDR in HT-144 cells. Our results therefore suggest that either topo I and II are both implicated in the repair of X-radiation damage, or that the lesions formed by CPT and VP-16 with DNA are able to impair the processing of X-radiation repair. In addition, we found that in the absence of the topo inhibitors, the two cell lines repaired similar amounts of PLD from an isosurvival level. Sk-Mel-3, however, repaired significantly increased SLD from an isosurvival level (about three-fold, p < 0.05) compared with HT-144.