To investigate further the alterations in pituitary-thyroid function seen during starvation, we have measured basal and TRH-stimulated serum levels of thyrotropin (TSH), prolactin (PRL), growth hormone, thyroxine (T4), triiodothyronine (T3), free T4, free T3, and reverse T3 during prolonged fasting in seven obese men. Fasting was associated with a significant decrease in serum (4, (3, and free T3, while there was an increase in serum reverse T3; these values tended to return toward pre-fast levels as the fast continued beyond 3 weeks. No significant changes were seen in basal serum TSH, PRL, growth hormone, or free T4. Although the TSH response to TRH was diminished during fasting, PRL, T4, and T3 responses were unchanged. In addition to transient alterations in the peripheral metabolism of T4, these findings suggest that alterations in the thyroid hormone binding capacity of serum carrier proteins may occur during fasting. The blunted TSH response to TRH despite reduction of serum T3 concentration suggests that subtle alterations in hypothalamic-pituitary function may also occur.