We compared the efficacy of clonidine and levetiracetam for treating tics in Tourette syndrome. Twelve subjects were enrolled; 10 (ages 8-27 years) with moderate to moderately severe tics completed a 15-week randomized, double-blind, flexible-dose crossover protocol. Initial medication doses were clonidine (0.05 mg, twice daily) or levetiracetam (10 mg/kg/day, divided twice daily). Doses were adjusted weekly, based on telephone assessment. The primary outcome measure was baseline-to-posttreatment (6-week) change in Total Tic Score of the Yale Global Tic Severity Scale. Secondary outcome measures included total Yale Global Tic Severity Scale and Clinical Global Impression scores and behavioral measures. The mean Total Tic Score improved significantly from baseline to posttreatment with clonidine (25.2 versus 21.8) compared with levetiracetam (22.7 versus 23.6) (P = 0.013). The mean total Yale Global Tic Severity Scale and Clinical Global Impression score did not change. For levetiracetam, no changes occurred in any scales. No significant change occurred in any secondary behavioral outcome measures for either group. The most commonly reported side effects were, for clonidine, sedation (n = 5), and for levetiracetam, irritability (n = 4). Treatment with clonidine, but not levetiracetam, resulted in a small reduction in Total Tic Score, with an effect size of 0.57.