Indomethacin (Ind) was administered to adult female rats to reduce endogenous prostaglandin (PG) synthesis in order to investigate the role of PG in thyroid hormone secretion. This treatment reduced thyroidal PGF levels (667.7 vs. 1822.1 pg/mg, P < .001). Although the plasma TSH [thyrotropin] concentrations were normal in the Ind-treated group (41.14 vs. 40.01 .mu.g/100 ml), dramatic decreases were observed in plasma T3 [triiodothyronine] (24.5 vs. 6.7 ng/100 ml, P < .001) and T4 [thyroxine] (5.6 vs. 0.7 .mu.g/100 ml, P < .001) levels. With normal TSH levels, the reduced thyroid hormone levels could be due to either decreased thyroid responsiveness to TSH, increased clearance rates for T3 and T4, or both. During Ind treatment, metabolic clearance rate of [125I]T4 was increased (2.6 vs. 1.3 ml/h per 100 g, P < .01), but clearance for [125I]T3 was unchanged. Although the percent of free T4 in serum was increased by the Ind (0.79 vs. 0.20%, P < .001), the concentration of free T4 in the Ind group was significantly lower (2.4 ng/100 ml) than that in the gelatin (Gel) treated control group (6.8 ng/100 ml, P < .001). Thyroid responsiveness to exogenous TSH was assessed by the increase in blood 125I levels, or by increases in plasma T3 and T4 levels. Exogenous TSH (10 mU[milliunits]/100 g BW [body wt.]) elicited a substantial rise in blood 125I levels (23%, P < .001) in the Gel-treated group, whereas there was no significant response in the Ind-treated group. In response to this same dose of TSH, plasma T4 levels in the Gel group rose significantly (from 3.3 to 5.5 .mu.g/100 ml, P < .01) whereas those in the Ind group rose only slightly (from 0.2 to 1.4 .mu.g/100 ml, P < .05). Plasma T3 levels rose markedly (from 19.2 to 63.5 ng/100 ml, P < .01) in the Gel group in response to a larger dose of TSH (100 mU/100 g BW); this response was completely blocked by the Ind treatment. The PG synthesis inhibitor Ind causes a dramatic decrease in circulating levels of T3 and T4; this effect is probably at least in part due to a marked reduction in thyroid responsiveness to TSH.