OBJECTIVE & STUDY DESIGN: In a parallel design, 23 and 22 healthy pre-menopausal women were randomly administered a contraceptive vaginal ring (CVR) delivering 150/15 μg Nestorone®/ethinyl estradiol (EE) daily or an oral contraceptive (OC) containing levonorgestrel and EE (150/30 μg) for three cycles, to compare the effects on C-reactive protein and other markers of inflammation. ANCOVA was performed with baseline values as covariate. RESULTS: The CVR caused [estimate of difference (95% CI), 109% (16–275%)] higher levels of CRP than the OC, while no difference was observed for leukocyte 1% (−13/+17%) and monocyte counts 6% (−9/+23%). The greater increase in CRP was confined to CVR recipients exhibiting low pre-treatment CRP-levels, whereas no difference was observed in the increases for recipients in the highest tertile of pre-treatment CRP levels. CONCLUSION: The difference in CRP rise in CVR and OC users does not correspond with the effects on other markers of inflammation and is most likely due to a specific difference in the effect of ethinyl-estradiol combined with nestorone in cases with low CRP.