Background Information concerning oxidative stress and low-grade inflammation in oral contraception users is scarce. We investigated relationships of oxidative stress and high-sensitivity C-reactive protein (hsCRP) in women by oral combined contraceptive (OC) use. Methods Caucasian Italian healthy non-obese women (n = 290; 100 OC-users; 190 non-OC-users; mean age 23.2 ± 4.7 years) were analyzed. Blood hydroperoxides, as oxidative stress biomarkers, were assessed by Free Oxygen Radical Test (FORT), and serum hsCRP was determined by routine methods. Results Oxidative stress levels were elevated (≥ 400 FORT Units) in 77.0% and 15.8% of OC-users and non-OC-users, respectively (odds ratio (OR) = 209, 95%CI = 60.9-715.4, p < 0.001); hsCRP levels ≥ 2.0 mg/L were found in 41.0% and 9.5% of OC-users and non-users, respectively (OR = 6.6, 95%CI 3.5–12.4, p < 0.001). Continuous hydroperoxides values in OC-users were 1.7-fold higher compared to non-users (median 472 versus 270 FORT Units, p < 0.001); OC-users had 3.7-fold higher hsCRP values compared to non-OC-users (median 1.31 versus 0.35 mg/L, p < 0.001). Hydroperoxides were strongly positively correlated to hsCRP in all women (rs=0.622, p < 0.001), in OC-users (rs=0.442, p < 0.001), and in non-OC-users (rs=0.426, p < 0.001). Women with hydroperoxides ≥ 400 FORT Units were 8 times as likely to have hsCRP ≥ 2 mg/L. In non-OC-users only, hydroperoxides values were positively correlated with weight and body mass index, but negatively correlated with red meat, fish and chocolate consumption. Conclusions Our cross-sectional observational study is the first finding a strong positive correlation of serum hydroperoxides with hsCRP, a marker of inflammation. Further research is needed to elucidate the potential role of these two biomarkers in OC-use side-effects, like thromboembolism.