<p>Tobacco dependence and abstinence self-efficacy are interrelated, and both are relevant variables for quitting smoking. Previous literature suggests that sex may also be a key factor in this relationship. This study aims to examine the relationship between tobacco dependence, self-efficacy and 12-months abstinence, and to explore the role of sex in this relationship. A total sample of 288 adult treatment-seeking daily smokers (<i>M</i>_age = 45.8, <i>SD</i> = 10.63; 62.5% females) was used. Participants were enrolled in a cognitive-behavioral smoking cessation treatment and were followed during a one-year period. We found a negative correlation between baseline tobacco dependence and smoking self-efficacy at the end of the intervention. Mediation analysis showed a significant indirect effect of tobacco dependence on quitting smoking via self-efficacy (<i>B</i> = -0.162, SE = 0.053, 95% BootCI [-0.287, -0.082]). We also found that sex significantly moderated the relationship between baseline tobacco dependence and self-efficacy at the end of the intervention. This result indicates that the indirect effect of tobacco dependence on quitting success through smoking self-efficacy was significant for females (<i>B</i> = -0.239, SE = 0.069, 95% BootCI [-0.402, -0.131]), but not for males. Self-efficacy has key role in the association between tobacco dependence and long-term abstinence, being particularly relevant for females. These findings contribute to understanding the role of tobacco dependence on abstinence, which is a well-known barrier to smoking cessation, and have several clinical implications as focusing on post-treatment self-efficacy in those with higher dependence could be relevant to improving the effectiveness of interventions to quit.</p>