The thalamus, with the highest density of nicotinic acetylcholine receptor (nAChR) in the brain, plays a central role in thalamo-cortical circuits that are implicated in nicotine addiction. However, little is known about whether the thalamo-cortical circuits are potentially predictive of smoking relapse. In the current study, a total of 125 participants (84 treatment-seeking male smokers and 41 age-matched male nonsmokers) were recruited. Structural and functional magnetic resonance images (MRI) were acquired from all participants. After a 12-week smoking cessation treatment with varenicline, the smokers were then divided into relapsers (n = 54) and nonrelapsers (n = 30). Then, we compared thalamic volume and seed-based thalamo-cortical resting state functional connectivity (rsFC) prior to the cessation treatment among relapsers, nonrelapsers and nonsmokers to investigate the associations between thalamic structure/function and smoking relapse. Increased thalamic volume was detected in smokers relative to nonsmokers, and in relapsers relative to nonrelapsers, especially on the left side. Moreover, decreased left thalamo-precuneus rsFC was detected in relapsers relative to nonrelapsers. Additionally, a logistic regression analysis showed that the thalamic volume and thalamo-precuneus rsFC predicted smoking relapse with an accuracy of 75.7%. These novel findings indicate that increased thalamic volume and decreased thalamo-precuneus rsFC are associated with smoking relapse, and these thalamic measures may be used to predict treatment efficacy of nicotine addiction and serve as a potential biomarker for personalized medicine.Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.