Context: Trichotillomania is characterized by repetitive hair pulling that causes noticeable hair loss. Data on the pharmacologic treatment of trichotillomania are limited to conflicting studies of serotonergic medications. N-acetylcysteine, an amino acid, seems to restore the extracellular glutamate concentration in the nucleus accumbens and, therefore, offers promise in the reduction of compulsive behavior. Objective: To determine the efficacy and tolerability of N-acetylcysteine in adults with trichotillomania. Design: Twelve-week, double-blind, placebo-controlled trial. Setting: Ambulatory care center. Patients: Fifty individuals with trichotillomania (45 women and 5 men; mean [SD] age, 34.3 [12.1] years). Interventions: N-acetylcysteine (dosing range, 1200-2400 mg/d) or placebo was administered for 12 weeks. Main Outcome Measures: Patients were assessed using the Massachusetts General Hospital Hair Pulling Scale, the Clinical Global Impression scale, the Psychiatric Institute Trichotillomania Scale, and measures of depression, anxiety, and psychosocial functioning. Outcomes were examined examined using analysis of variance modeling analyses and linear regression in an intention-to-treat population. Results: Patients assigned to receive N-acetylcysteine had significantly greater reductions in hair-pulling symptoms as measured using the Massachusetts General Hospital Hair Pulling Scale (P < .001) and the Psychiatric Institute Trichotillomania Scale (P=.001). Fifty-six percent of patients "much or very much improved" with N-acetylcysteine use compared with 16% taking placebo (P=.003). Significant improvement was initially noted after 9 weeks of treatment. Conclusions: This study, the first to our knowledge that examines the efficacy of a glutamatergic agent in the treatment of trichotillomania, found that N-acetylcysteine demonstrated statistically significant reductions in trichotillomania symptoms. No adverse events occurred in the N-acetylcysteine group, and N-acetylcysteine was well tolerated. Pharmacologic modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors. Trial Registration: http://www.clinicaltrials.gov Identifier: NCT00354770.