Resting peripheral blood lymphocytes have a large number of single strand breaks and are especially sensitive to DNA damaging agents. Deoxyadenosine, an adenosine deaminase substrate, in combination with the adenosine deaminase inhibitor deoxycoformycin, causes accumulation of single strand breaks in resting peripheral blood lymphocytes. The induction of single strand breaks by deoxyadenosine is the result of the accumulation of large amounts of intracellular dATP, which creates imbalance in deoxynucleoside triphosphate levels. This imbalance in deoxynucleoside triphosphate levels interferes with the repair of single strand breaks in deoxyadenosine treated cells. Deoxyadenosine acts synergistically with N-methyl-N'-nitro-N-nitrosoguanidine, a DNA alkylating agent, by inhibiting the repair of N-methyl-N'-nitro-N-nitrosoguanidine-induced single strand breaks. We propose that the increased sensitivity of resting peripheral blood lymphocytes to deoxyadenosine and possibly to other DNA damaging agents may be associated with impaired DNA repair ability due to imbalance in intracellular levels of deoxynucleoside triphosphate.