The restless legs syndrome is a sensory and motor disorder of evening, repose, and sleep. The cardinal features include (a) restlessness, which is frequently associated with (b) dysesthesias, (c) myoclonic jerks and other dyskinesias while awake, (d) periodic movements of sleep, and (e) sleep disturbances. We have recently had the opportunity to study two patients severely affected by this syndrome whose family histories are consistent with dominant inheritance. Both patients serendipitously discovered that their symptoms responded uniquely well to opiate medication. Both patients were studied extensively with electrophysiological and videotape monitoring, and their movements were characterized. In both patients, all elements of the syndrome responded to opiates, with marked relief of symptoms and without any significant side effects. The specific opiate antagonist naloxone blocked the therapeutic benefit of the opiates. Our findings support the involvement of the endogenous opiate system in the pathogenesis of restless legs and related dyskinesias and suggest that opiate therapy may be a potentially valuable treatment for this sometimes disabling syndrome.