Background and Aims: Nicotine dependence (ND)-induced anxiety might be modulated by genetic polymorphisms. The gene-by-environment interaction can be fitted into the diathesis-stress and differential susceptibility models. Nevertheless, knowledge of the interaction between adiponectin (ADPN) polymorphisms and ND on the incident mental disorder is currently scarce. This study aims to understand the role of ADPN rs266729 on anxiety in patients with ND while elucidating the psychology model and the various reactions across genotypes. Methods: We included 315 Chinese males with confirmed ND, measured using the Fagerstrom test for nicotine dependence (FTND). Anxiety was assessed using the Self-rating Anxiety Scale. Genomic DNA was extracted and genotyped from peripheral blood. Hierarchical regression models were used to test the interactions. Results: There was a significant interaction between ADPN rs266729 and ND (\beta = –0.19, p 0.05). The CC homozygote was more likely to be affected by ND-induced anxiety (\beta = 0.14, t = 4.43, p 0.01). Re-parameterized regression models revealed that the interaction between ADPN rs266729 and ND could fit the strong differential susceptibility model (R{}^2 = 0.05, p 0.001). Conclusions: ADPN rs266729 was correlated with susceptibility to anxiety symptoms among male adults with ND and could fit the differential susceptibility model. The CC homozygote of rs266729 was a plasticity factor that increased anxiety symptoms in individuals with ND.