We have hypothesized that symptoms of Tourette Syndrome (TS) may represent D2 (dopamine-2) receptor hyperactivity. We treated 4 TS patients with piquindone, a novel D2 receptor antagonist designed via a 3-dimensional model of dopamine receptors. All 4 patients experienced a clinically obvious reduction of tics. Sedation that decreased over time was the only adverse effect. Haloperidol, the current treatment of choice of TS, is limited primarily by its extrapyramidal side-effects. However, piquindone produced therapeutic effects without disabling side-effects. Motor tics responded at lower doses than vocal tics. All patients expressed a strong subjective preference for piquindone over haloperidol. Our results suggest that therapeutic efficacy of a D2 receptor antagonist in TS can be achieved without production of disabling extrapyramidal-side effects. These results also support the proposal that TS may be mediated by hyperactive D2 receptors.