BACKGROUND: Smoking cessation rates with current therapy are suboptimal. One class of drugs that may improve cessation is the tricyclics. OBJECTIVE: To add nortriptyline hydrochloride to a behavioral smoking cessation program to enhance cessation rates and reduce withdrawal symptoms. SUBJECTS AND METHODS: We conducted a randomized, double-blind, placebo-controlled trial at an affiliated Department of Veterans Affairs Medical Center and an Army Medical Center. Subjects were aged 18 through 70 years, smoked 10 or more cigarettes per day, and were without current major depression. Nortriptyline hydrochloride or matched placebo was started at 25 mg before bed 10 days prior to quit day and titrated to 75 mg/d or to the maximal tolerated dose. The behavioral intervention consisted of 2 group sessions and 12 individual follow-up visits. Withdrawal symptoms were measured using a daily diary, and smoking cessation was defined as self-reported abstinence, expired carbon monoxide of 9 ppm or less, and a 6-month urine cotinine level of less than 50 ng/mL. RESULTS: A total of 214 patients were randomized (108 to nortriptyline and 106 to placebo). There was a significant reduction in several withdrawal symptoms including anxious/tense, anger/irritability, difficulty concentrating, restlessness, and impatience by day 8 after quit day in the nortriptyline group. The cessation rate at 6 months was 15 (14%) of 108 and 3 (3%) of 106, respectively (P = .003; absolute difference, 11%; 95% confidence interval, -18% to -4%). Nortriptyline caused frequent adverse effects, including dry mouth (64%) and dysgeusia (20%). CONCLUSIONS: We conclude that nortriptyline led to an increased short-term cessation rate compared with placebo. In addition, there were significant, but relatively small, reductions in withdrawal symptoms. Nortriptyline may represent a new therapeutic approach to smoking cessation.