We report on the cause and effect relationship of restless legs syndrome (RLS) with L-thyroxine treatment in a hypothyroid patient with low serum ferritin. Upon challenge and withdrawal of L-thyroxine, there was a significant change in the International Restless Legs Syndrome Study Group severity score (26/40 to 6/40), the periodic limb movements (PMLS) index (20/hour to 10/hour), the number of arousals due to PLMS (59 to 22), sleep efficiency (74 to 85%), and biochemical parameters. RLS symptoms can complicate thyroxine replacement in at-risk hypothyroid patients with low serum ferritin. Early diagnosis and iron replacement could significantly reduce patient morbidity. © 2004 Movement Disorder Society