Natural killer (NK) activity of human mononuclear cells is sensitive to inhibition by radiation, under the control of polymorphic X linked genes. In order to define the mechanism of this inhibition, we have evaluated the ability of treatments known to damage DNA to inhibit NK activity. The alkylating agents streptozotocin (SZ) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were potent inhibitors of NK activity. Further, a specific competitive inhibitor of adenosine diphosphoribosyl polymerase (ADPRP), 3-aminobenzamide, was able to prevent inhibition by gamma-radiation, UV radiation, and the two alkylating drugs, SZ and MNNG, suggesting the ADPRP, known to be activated by DNA strand breakage, mediates the inhibition by these treatments. NK activity of radioresistant subjects was somewhat more resistant to inhibition by SZ or UVR when compared to radiosensitive NK activity but neither of these treatments gave the clear phenotypic distinction of gamma-radiation, suggesting that chemical strand breakage does not precisely model gamma-radiation and also that the mechanism of UVR inhibition may differ from that of gamma-radiation. These results indicate a role for activation of ADPRP in the inhibitory effect of UV and gamma-radiation on human NK activity and suggest that the biochemical basis for polymorphism in the sensitivity of NK activity to gamma-radiation will be found in the sensitivity to ADPRP activation or the level of activation of this enzyme, known to be the key to DNA repair.