Cell-free incorporation of (14C) leucine into protein was 38% greater for cerebral cortical microsomes from 22-day old neonatally thyroidectomized rats compared to littermate controls. In contrast, incorporation by liver microsomes of hypothyroid rats was 33% lower compared to controls, confirming their deficient hormonal state. Incubation of cerebral microsomes from either hypothyroid or euthyroid rats with both homologous and heterologous pH 5 enzyme fractions clearly implicated the pH 5 fraction as the source of the apparent increase in protein synthetic capacity in the hypothyroid brain. Daily administration of L-thyroxine (20 microgram/100 g body wt) to hypothyroid animals between 22 and 25 days of age produced an additional increase in (14C) leucine incorporation into protein by cerebral microsomes, whereas the cell-free protein synthesis rate of euthyroid rats was unaffected by similar hormonal treatment. Liver preparations from both hypothyroid and euthyroid rats exhibited the expected increase in cell-free protein synthesis following thyroxine administration. The results support the hypothesis that the young hypothyroid brain exhibits delayed maturation and that thyroid hormones play a regulatory role in cerebral protein synthesis during a defined developmental period.