OBJECTIVE. The aim of this study was to determine whether thyroxine treatment would improve nerve conduction in infants with Down syndrome. METHODS. A single-center, nationwide, randomized, double-blind, clinical trial was performed. Neonates with Down syndrome were assigned randomly to thyroxine (N = 99) or placebo (N = 97) treatment for 2 years. Daily thyroxine doses were adjusted regularly to maintain plasma thyrotropin levels in the normal range and free thyroxine concentrations in the high-normal range. The outcome measures were nerve conduction velocity and central conduction time, determined through median nerve somatosensory evoked potential recording, at the age of 24 months. RESULTS. At the age of 24 months, somatosensory evoked potential recordings for 81 thyroxine-treated and 84 placebo-treated infants were available for analysis. Nerve conduction velocity and central conduction time did not differ significantly between the 2 treatment groups (nerve conduction velocity: thyroxine: 51.0 m/second; placebo: 50.1 m/second; difference: 0.9 m/second; central conduction time: thyroxine: 8.83 milliseconds; placebo: 8.73 milliseconds; difference: 0.1 milliseconds). CONCLUSIONS. Postnatal thyroxine treatment of infants with Down syndrome did not alter somatosensory evoked potential-measured peripheral or central nerve conduction significantly. The absence of favorable effects suggests that pathologic mechanisms other than mild postnatal hypothyroidism underlie the impaired nerve conduction. The absence of adverse effects suggests that longstanding plasma free thyroxine concentrations in the high-normal range are not harmful to nerve maturation.