We examined in vitro the effect of high, but clinically achievable and non-toxic, concentrations of 2'-deoxycytidine (dCyd) (greater than or equal to 100 mumols/l on the metabolism and cytotoxicity of 2',3'-dideoxycytidine (DDC) in normal human bone marrow mononuclear cells (BMMCs) and a cultured T-lymphocyte (HUT-102) cell line. Colony formation in semi-solid medium by bone marrow progenitor cells (CFU-GM and CFU-GEMM) was significantly protected by dCyd against the cytotoxic effects of high doses of DDC. In contrast, in HIV-infected HUT-102 cells, anti-HIV effect of DDC (10 mumols/l) was preserved in the presence of 100 mumols/l dCyd but partially reversed by higher levels of dCyd. dCyd reduced the generation of DDC triphosphate (DDC-TP) relative to dCyd triphosphate (dCTP) pools to a significantly greater extent in BMMCs versus HUT-102 cells. This might explain dCyd-mediated abrogation of DDC cytotoxicity against marrow progenitor cells with relative preservation of its anti-HIV-1 activity in HUT-102 cells.