OBJECTIVES: The objective of this paper is to evaluate the efficacy of nortriptyline for smoking cessation compared to placebo and bupropion sustained release. DATA SOURCES: Randomized trials were identified by (1) checking electronic and (2) online publicly accessible registers of clinical trials; (3) searching references of identified studies and screening abstract books of conferences and symposia, and (4) personal communication with the first authors of identified papers. REVIEW METHODS: We included randomized trials in which nortriptyline was compared to placebo or bupropion hydrochloride SR. The main clinical outcome measure was (at least) 6-month prolonged abstinence, confirmed with a biochemical test. To investigate the efficacy of nortriptyline in time, we calculated the percentage of smokers who relapsed in time. RESULTS: We identified five randomized trials, including 861 smokers. Compared to placebo medication, nortriptyline resulted in significantly higher prolonged abstinence rates after at least 6 months [relative risk (RR) = 2.4, 95% CI 1.7-3.6; RD = 0.11, 95% CI 0.07-0.15]. The difference in efficacy between nortriptyline and placebo was highest in the first months after the target quit date. However, the number of people who remained abstinent decreased substantially and significantly faster over time in the nortriptyline group. Although bupropion resulted in higher abstinence rates compared with nortriptyline, the difference was not statistically significant (RR = 1.7, 95% CI 0.7-4.1). CONCLUSION: This systematic review and meta-analysis shows that the use of nortriptyline for smoking cessation resulted in higher prolonged abstinence rates after at least 6 months compared to placebo treatment. Furthermore, the use of nortriptyline for smoking cessation is well tolerated and safe. As a result, we believe health care professionals should be recommended to prescribe nortriptyline as a first-line therapy for smoking cessation, also because of the much lower cost of nortriptyline compared to bupropion SR.