Some clinical data suggest that etoposide and cisplatin may be synergistic against certain types of tumors. Since studies of the process are both easier and more precise in laboratory systems, we have used V79 spheroids as a model to quantify the interaction of the drugs in cycling and noncycling, aerobic, and hypoxic cell subpopulations. The degree of interaction between etoposide and cisplatin in this system, quantified using the median-effect analysis, was highly dependent on the overall treatment toxicity, and to a lesser extent, the subpopulation of cells assessed. Synergism was demonstrated for relatively modest (1 decade) cell kills achievable at clinically relevant drug doses; increasing the toxicity of the combination treatment by increasing the cisplatin level produced a greater relative gain in the noncycling and hypoxic cells than in the aerobic, cycling cells of the spheroids.