To determine the impact on blood markers of thrombosis of switching from an oral to a transdermal or vaginal combined hormonal contraceptive method. Multicenter, randomized, open label, comparator. Current healthy oral contraceptive (OC) users randomized to switch to either a vaginal ring (NuvaRing®) or skin patch (OrthoEvra®) contraceptive in an acceptability study were asked to participate in a substudy investigating the effect of these products on markers of thrombosis. Blood samples were obtained for Sex Hormone Binding Globulin, (SHBG), total Protein S, and Activated Protein C resistance (APC-r) before, and 4 months after switching to the new method. Following separation of serum and plasma, samples were frozen on dry ice, and stored between – 70 to –80°C until shipment to a central lab for analysis. Changes in mean levels of the markers from baseline were compared using separate repeated measures analysis for the ring and patch groups. A total of 142 reproductive age women were enrolled at three study sites. Of these, 120 completed 4 cycles and contributed both blood samples. SHBG increased significantly from baseline values in the women who switched to the Patch (mean (SD) change +29.9 nM (74.8), P=0.005) but not those who switched to the Ring (−1.6 (60.7), P=0.83). Coherent with this, Protein S decreased significantly from baseline values in the Patch (mean change −7.1% (18.3), P=0.006) but increased significantly in those who switched to the Ring (+5.3% (17.1), P=0.014) The APC-r ratio did not undergo a significant change from baseline in either group [(Ring +0.02 (0.48), P=0.7), Patch +0.06 (0.43), P=0.3)]. While there were no significant differences between groups in baseline values of SHBG, Protein S, or APC-r, after 4 cycles SHBG was significantly higher (187.5 (75.9), 146 (54.2), P=0.001) and Protein S significantly lower (81.8 (18.2), 93.6 (18.2), P=0.001) in Patch than in Ring users. The APC-r ratio was not different (2.99 (0.52) Patch, 3.09 (0.51) Ring, P=0.3). OC users who switch to the patch undergo a change in hemostatic balance (decreased Protein S, increased SHBG) consistent with a more prothrombotic state. Further epidemiological studies of thrombosis risk in patch users are warranted to determine the clinical significance.