Abstract: Background: Surrogate indexes of insulin resistance (IR) are less expensive than the euglycemic glucose clamp. The simultaneous impact of sex and gender, smoking, and combined oral contraceptives (COC) on IR surrogate indexes was studied in a cohort of healthy young men and women (stratified in COC-free women and COC users). Methods: Glycemia, insulin, C-peptide, TG, and HDL were measured in serum samples and used to calculate IGR, HOMA-IR-IR, QUICKI, FIRI, METS-IR, TG, and MCAi. Results: Men had higher BMI, glycemia, TG, METS-IR, TyG, and lower HDL than COC-free women and they had lower IGR and higher METS-IR and MCAi than COC users. TG, HDL, and TyG were lower and MCAi is higher in COC-free women than in COC users. In non-smokers, men had higher BMI and METS-IR and lower HDL than both cohorts of women. COC-free women showed a lower TyG index than men and COC women and lower TG, HDL, and IGR. MCAi was higher in COC-free women than in COC users. Smoking reduced sex and gender differences: HDL was lower in men than COC users and IGR was lower in men than COC-free women. Intra-sex differences were reported only in COC-free women: smokers had higher insulin, C-peptide, TG, and IGR and lower MCAi than non-smokers. Cluster analysis evidenced a significant separation between the sexes and smokers and non-smokers. Conclusions: Smoking leads to changes in the phenotype of both men and women, as well as COC in women; they should be considered independent variables in clinical studies given, representing a fundamental cornerstone in the personalization of prevention and care.