A high incidence of transient neonatal hypothyroidism has been observed in premature infants after routine skin cleansing with iodine. Because these reports have been predominantly from Europe, a borderline, iodine-deficient area, we wished to determine whether this was also true in North America, an iodine-sufficient area. A prospective, controlled study was performed in premature babies < or = 36 weeks gestation admitted to a neonatal intensive care nursery. Thyroxine (T4) and thyrotropin (TSH) were measured at day 1, days 4 to 6, and 10 to 12 after skin preparation with iodine or with a noniodine-containing antiseptic solution (chlorhexidine) that served as control. If repeat cleansing was required, this sequence was repeated. Urinary iodine was quantitated on days 1 to 3 to estimate iodine exposure. There was no difference in the mean T4 concentration at any of the time points evaluated nor in the incidence of transient hypothyroidism between the iodine-exposed (2/17) and control babies (0/14) despite urinary iodine excretion up to 88 times the control value. Unexpectedly 5 iodine-exposed but 0 control babies developed severe hypothyroxinemia (T4 < 40 nmol/L), compatible with the sick euthyroid syndrome; one of them died. We conclude that, unlike in Europe, transient hypothyroidism is not a common sequela of routine skin cleansing with iodine in premature newborn infants in North America. This difference in incidence may be due to prior iodine status. Whether excessive iodine absorption in premature infants is associated with thyroid-independent toxic effects remains to be clarified.