This study was performed to characterize the role of thyroxine (T4) in the regulation of fetal adipose tissue metabolism. On day 70 of gestation, pig fetuses were hypophysectomized (hypoxed) by microcauterization. Both hypoxed and intact fetuses were implanted subcutaneously with T4 pellets or received no hormone replacement. Fetuses were removed by laparotomy on day 90 of gestation. Additional fetuses were hypoxed on day 70, implanted with T4 pellets on day 90 and removed on day 105 of gestation. Serum T4 levels were similar in hypox + T4 and intact + T4 fetuses and increased in both groups relative to their respective controls. T4 supplementation restored the lipolytic response to isoproterenol and enhanced the response to dibutyryl cyclic AMP at 90 days in hypoxed animals but had no effect on basal or stimulated lipolysis in intact fetuses. T4 induced a dramatic increase in lipogenesis in hypoxed fetuses when administered during either fetal period and produced a slight though significant increase in basal lipogenesis in intact fetuses when administered from days 70 to 90 of gestation. However, T4 had no effect on basal or insulin-stimulated lipogenesis in intact fetuses when administered from days 90 to 105 of gestation. These results indicate that T4 may have a primary influence on fetal adipose tissue metabolism only in the absence of inhibition from counterregulatory hormones of pituitary origin.