This study reports the effects of the nucleoside analogs dideoxyinosine (DDI) and 3'-azido-3'deoxythymidine (AZT) on mammalian embryonic development. When administered to pregnant mice (at concentrations ranging from 10 to 300 mg/kg/day), through all or part of gestation, AZT and DDI did not result in any visible effect on mouse embryos nor did they cause any obvious malformation or defect at birth or during postnatal growth. Similarly, when embryonic or fetal mouse or human cells (from brain, limb buds, or different organ rudiments) were exposed to AZT or DDI in vitro, cytotoxicity was observed only in the mM range, with AZT showing slightly higher cytotoxicity and brain cells appearing slightly more sensitive to both nucleosides. However, even in cultures treated with very high concentrations of AZT or DDI, the reduction in the number of terminally differentiated skeletal myotubes, cardiocytes, neurons, and chondrocytes was similar to the reduction in the total number of cells, indicating that AZT and DDI did not selectively inhibit differentiation of any of the above-mentioned cell types. Finally, preimplantation mouse embryos (at the 2-cell or 4-cell stage), treated in vitro with micromolar concentrations of AZT, were arrested at the 4-cell stage. DDI or other nucleoside analogs tested did not have this effect.