The effects of several nitrobenzene derivatives on the O2 utilization and radiation response of multicell [Chinese hamster] spheroids were determined. In this system, the best radiosensitizer was nitrotoluene, previously reported to be a poor sensitizer of axonic cells in monolayer cultures. The sensitization of the spheroid is interpreted as due to nitrotoluene''s immediate inhibitory effect on cellular O2 utilization resulting in a reoxygenation of the centrally located cells. The axonic radiosensitizer dinitrobenzonitrile markedly stimulated O2 utilization producing immediate protection, presumably because the hypoxic fraction of the spheroid was increased. Some radiosensitization occurred with dinitrobenzonitrile at higher concentrations and after longer period of exposure to the drug. The altered radiation response, caused by nitrotoluene or dinitrobenzonitrile, agreed fairly well with the theoretical prediction of the radiation response as a function of O2 utilization. A 3rd anoxic sensitizer, dinitrophenylpyridinium chloride, which possesses the greatest electron affinity (Hammett constant) but has little effect on O2 utilization, produced only a slight sensitization of the spheroids. These results indicate that electron affinity alone is not a good criterion for predicting the effects of drugs on the radiation response of complex systems consisting of eutoxic and hypoxic cells. Effects of O2 utilization may extensively modify the drug enhanced radiosensitization in multicelluar systems.