The effect of triiodothyronine (T3) on somatostatin (SS) mRNA levels in cultured fetal rat cerebrocortical cells was studied. Two different experimental approaches were sought. They differed in the length of time in which cells were deprived of thyroid hormones prior to the addition of exogenous T3. When the cells were not deprived of thyroid hormones, T3 caused a dose-related decrease in SS mRNA content at all doses tested. However, when the cells were deprived of T3 for 24 h, a biphasic effect was observed. These findings suggest that T3 regulates SS gene expression in fetal cultured cerebrocortical cells.