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IR risk factors are numerous and include smoking, sex, and gender. Smoking, directly and indirectly, induces IR in a dose-dependent way [] that is affected by sex and gender [,]. In real life, smoking can modify male and female phenotypes although the consequences of this variation probably occur differently in men and women [,]. As already mentioned, IR in women is affected by exogenous and endogenous sex hormones [,], and numerous interactions are described between combined oral contraceptives (COC) and smoking [,], including a major thrombotic risk []. Therefore, the present study aimed to investigate the simultaneous impact of sex, gender, and smoking on surrogate indexes of IR in a cohort of healthy young men and women. Furthermore, the female cohort is further stratified in COC-free women and COC users to analyze the impact on IR of the combination of COC and smoking.