Background <p>Affective disorders often co-occur with behavioral risk factors like smoking, and chronic metabolic disorders like obesity or type 2 diabetes. One possible regulation factor in these comorbidities could be resistin, an adipokine involved in inflammation and insulin resistance. Here, we investigate these factors in depressed patients, in a sex-sensitive approach.</p> Methods <p>We assessed depression symptoms in a sex-balanced cohort using the Beck Depression Inventory-II and the Male Depression Risk Scale. We further evaluated smoking behavior using self-report and the Fagerström Test for Nicotine Dependence. Resistin levels were measured in blood samples.</p> Results <p>Higher resistin levels were associated with increased risk of major depressive disorder (MDD) in a sex- and smoking-dependent manner, with the strongest effect observed in female smokers and ex-smokers. No association was found between resistin and depression severity, while alcohol use emerged as the strongest predictor of masculine depression symptoms.</p> Conclusion <p>This study demonstrates that resistin interacts with smoking and sex to increase MDD risk, particularly in female smokers/ex-smokers, highlighting the importance of preventive strategies targeting depression risk in women with comorbid risk behaviors such as smoking.</p> Trial registration <p>German Clinical Trials Register ID DRKS00015291, registration date 2020-01-06, retrospectively registered.</p>