Evidence that the thyroid may play a role in the pathogenesis of attention deficit hyperactivity disorder (ADHD) comes from observations that 48% to 73% of children with the syndrome of resistance to thyroid hormone (RTH) have ADHD. Casual observations in subjects with RTH have suggested that treatment with thyroid hormone may improve the symptoms of ADHD. The aim of this study was to determine whether thyroid hormone has a beneficial effect on the behavior of children with RTH. A prospective, randomized, double-blinded, placebo-controlled, cross-over study was conducted to evaluate the effect of the rapid acting thyroid hormone, liothyronine (L-T3), on the behavior of 8 children with ADHD + RTH, and 9 children with ADHD and normal thyroid function (ADHD Only). Parent and teacher ratings of hyperactivity (Conners scale) and a computerized continuous performance test (CPT) were used as objective measures of hyperactivity, attention and impulsivity. L-T3 had no effect on Conners Hyperactivity Index in 7 of 9 children with ADHD Only; it caused improvement and deterioration in 1 subject each. In contrast, the rating in 5 of 8 subjects with ADHD + RTH showed improvement, whereas 3 of 8 subjects remained unchanged. L-T3 was associated with increased commission errors in 5 of 8 children with ADHD Only and decreased commission errors in 4 of 7 with ADHD + RTH. In children with RTH and ADHD, particularly those that exhibit hyperactivity, L-T3 in supraphysiological doses may be beneficial in reducing hyperactivity and impulsivity. In the majority of children with ADHD who do not have RTH, L-T3 treatment has no effect or may be detrimental.