The interactions between ionizing radiation and etoposide were probed using asynchronous growing V-79 fibroblasts. Synergistic cell kill was observed as gamma-rays were applied prior to or concomitantly with the drug. Three major determinants of enhanced cytotoxicity in combined treatment were identified. The kinetic analysis of radiation recovery bore evidence of two repair interaction mechanisms. First, rapidly repairable radiation-induced DNA damage was fixed into lethal lesions by etoposide, thus giving rise to marked supra-additive interaction under concomitant radiation-drug exposure. Second, cells arrested in G2 phase following radiation proved hypersensitive to the cytotoxic effect of etoposide. It is proposed that either topoisomerase II alpha is closely involved in some rapid DNA repair pathway operating during all phases of the cell cycle, and even further involved in DNA repair acting within the radiation-induced G2 block, or that the lesions induced by etoposide are able to impair these processes. The shoulder of the radiation survival curve was abolished as gamma-rays and drug were applied at 1-h intervals. This effect, corresponding to mode II additivity from isobologram determinations, appeared to be correlated with a differential sensitivity of the various phases of the cell cycle to drug and radiation.