The effect of deoxycytidine (dCyd) on the inhibitory effects of two antileukemic nucleoside analogs, 5-aza-2'-deoxycytidine and ara-5-aza-Cyd, toward the clonogenic growth of normal human bone marrow progenitors (CFU-GM) and leukemic blast progenitors (L-CFU) was examined. Continuous exposure of cells to 10(-6)-10(-5) M 5-aza-deoxycytidine or 10(-5)-5 x 10(-5) M ara-5-aza-Cyd in conjunction with a 10- 100-fold excess of dCyd resulted in significantly greater restoration of CFU-GM growth than L-CFU colony formation at each dose relationship. Normal bone marrow mononuclear cells exposed to 10(-3) M dCyd for 4 hr (along with 5-aza-dCyd or ara-5-aza-Cyd) exhibited intracellular deoxycytidine triphosphate (dCTP) pools 20-fold higher than their leukemic counterparts. However, this finding was not associated with enhanced analog incorporation into leukemic cell DNA. These results suggest that high concentrations of dCyd preferentially protect normal versus leukemic progenitor cells from the inhibitory actions of 5-aza-dCyd and ara-5-aza-Cyd. They also raise the possibility that this in vitro selectivity may be related to enhanced expansion of dCTP pools in normal bone marrow elements and involves factors other than differential short-term analog incorporation into DNA.