Previous experiments have indicated that zidovudine is cytotoxic to early murine embryos both in vivo and in vitro. Newer nucleoside analogs (ddI, ddC, and d4T) with antiretroviral activity were tested to determine whether they had similar toxicity. Exposure of two-cell embryos to each of these three drugs inhibited blastocyst formation only at concentrations > or = to 100 microM. Sublethal preblastocyst exposure to d4T resulted in failure to develop beyond the blastocyst stage at 10 microM; no effect was seen with ddC or ddI at concentrations up to 100 microM. In each instance, however, cytotoxicity of all three drugs was significantly less than with zidovudine at equivalent concentration. These experiments suggest that newer antiretroviral nucleosides may be safer to use in early pregnancy than zidovudine.