C-reactive protein (CRP), smoking, and oral contraceptive (OC) use are associated with CVD risk in adults. This study examines the effect of smoking on high-sensitivity CRP (hs-CRP) levels, and the interactive effects of sex and OC use on this relationship in an adolescent cohort. A total of 1,050 adolescents (mean age 17 ± 0.25 years) from the Western Australian Pregnancy Cohort (Raine) Study had anthropometric, lifestyle, and metabolic measures recorded. The association between smoking status and log-transformed hs-CRP was analyzed using multivariable Tobit linear regression models, with adjustment for adiposity, lifestyle, and early-life confounders. A threelevel variable (girls not using OCs, girls using OCs, and boys) was employed to assess the interactive effects of sex, OC use, and smoking. Smoking associated with higher hs-CRP levels in girls not using OCs (b = 0.571; P = 0.001), but not in girls using OCs (b =-0.117; P = 0.598) or in boys (b = 0.183; P = 0.2). OC use in nonsmoking girls was the strongest factor associated with higher hs-CRP levels (b = 1.189; P <0.001). This study has demonstrated a more robust effect of smoking on hs-CRP levels in girls not using OCs compared with boys. The findings may explain why CVD risk conferred by smoking is higher in women than in men. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.