1. 1. Mature male and female rats respond in a similar fashion to a single dose of ethionine by the following changes in the liver: (a) marked depression of ATP concentration, (b) large accumulation of S-adenosylethionine and (c) severe inhibition of radioactive orotate incorporation into nuclear and microsomal RNA. 2. 2. However, a divergence in the response between the sexes is seen in hepatic protein synthesis. In the female rat, there is a rapid and marked inhibition of protein synthesis both in vivo and in vitro accompanied by a breakup of polysomes into monomers. In contrast, in male rats there is much less inhibition of protein synthesis in vivo, no inhibition in vitro and only a slight loss of polysomes. The unusual resistance of the polysomes from the male to the ATP deficiency lasts for at least 24 h. At that time, the male shows less depression of ATP concentration and a decrease in S-adenosylethionine content of the liver when compared to the female. The possible usefulness of this model for the analysis of some aspects of polysome metabolism in the intact cell is briefly discussed. © 1969.