The object was to study thyroid function in neonates with severe respiratory failure on extracorporeal membrane oxygenation (ECMO) and determine whether abnormal thyroid function correlates with prognosis. Total and free thyroxine (T-4, FT4), total and free triiodothyronine (T-3, FT3), reverse triiodothyronine (rT(3)), thyroid-stimulating hormone, and thyroxine binding globulin were measured in 14 newborn infants with severe respiratory failure (age 1-30 days) from samples collected before anesthesia for cannula placement, at 30, 60, and 360 min after initiation of ECMO, and on days 2, 4, 6, and 8. The patients were divided into survivors and non-survivors for statistical analyses. No differences were noted between survivors and nonsurvivors in the pre-ECMO mean serum concentrations of the thyroid function tests analyzed. In nine survivors, mean serum T-4, FT4, T-3, FT3, and rT(3) all declined significantly within 30-60 min after initiation of ECMO, compared to baseline values. The values for all mean serum concentrations recovered completely and exceeded baseline between days 2 and 8. In five non-survivors, the decline of all mean serum values was not statistically significant and recovery to baseline was not achieved. The ratios of mean serum concentration of rT(3)/FT3 were significantly different between survivors and non-survivors across all times during the ECMO course (p<0.0005). These findings indicate that abnormalities in thyroid function occur in neonates with severe respiratory failure on ECMO and that the rT(3)/FT3 ratio correlates with prognosis over the ECMO course. Survival was associated with a significant reduction of serum thyroid hormone concentrations followed by recovery. We speculate that, in neonates with respiratory failure on ECMO, adaptive mechanisms which enhance survival include the capacity to down-regulate the pituitary-thyroid axis.